A Global Bibliometric Study of Current Bladder Cancer Cell Death Research

Zhi-wenCao5

Yue-yiChen1

Nan-xiFu6

Fu-ruiFu3

Sen-jieShi3

Hong-yuWang3✉

Chuang-longXu2,4✉

ChuanglongXu1Emailmqxcl@163.com

HongyuWang1Emailwanghongyu2026@163.com

1School of NursingNingxia Medical UniversityYinchuanChina

2Ningxia Hui Autonomous Traditional Chinese Medicine Hospital and Chinese Medicine Research InstituteYinchuanChina

3Longhua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina

4Guizhou University of Traditional Chinese MedicineGuiyangChina

Nanchang Hongdu Traditional Chinese Medicine HospitalJiangxiChina

6Jinan UniversityGuangzhouChina

Zhi-wen Cao^5†,Yue-yi Chen^1†, Nan-xi Fu^6†, Fu-rui Fu³,Sen-jie Shi³, Hong-yu Wang^3*, Chuang-long Xu^2,4*

¹School of Nursing, Ningxia Medical University, Yinchuan, China

²Ningxia Hui Autonomous Traditional Chinese Medicine Hospital and Chinese Medicine Research Institute, Yinchuan, China

³Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China

⁴Guizhou University of Traditional Chinese Medicine, Guiyang, China

⁵Nanchang Hongdu Traditional Chinese Medicine Hospital, Jiangxi, China

⁶Jinan University, Guangzhou, China

*Correspondence: Chuanglong Xu, Email: mqxcl@163.com, Hongyu Wang, Email: wanghongyu2026@163.com

Zhi-wen Cao, Yue-yi Chen and Nan-xi Fu contributed equally to this work.

Abstract

Cell death mechanisms offer therapeutic strategies for bladder cancer, yet lack comprehensive bibliometric analysis. Map global research trends and hotspots in bladder cancer cell death mechanisms via bibliometrics. We analyzed 5,392 publications (1991–2024) from Web of Science using VOSviewer (co-authorship/keyword clustering), CiteSpace (citation bursts), and GraphPad Prism (statistics). Metrics included: (1) Temporal trends, (2) Country/institution contributions, (3) Journal impact, (4) Citation dynamics, (5) Collaboration networks, (6) Conceptual hotspots. China and the US led research output. Top institutions:University of Texas System (USA; 178 publications), UTMD Anderson Cancer Center (USA; 123), Nanjing Medical University (China; 122), Journal of Urology had the highest output (106 publications); Cancer Research (IF:12.5) the highest impact. Kim Wun-Jae was the most productive author (37 articles); Jemal A the most co-cited (446 citations). Keyword and citation analyses revealed emerging integration of cell death mechanisms with immunotherapy (IT) and photodynamic therapy (PDT) to overcome chemoresistance. This study delineates the evolution of bladder cancer cell death research and identifies IT/PDT as promising resistance-overcoming strategies grounded in targeted cell death pathways.

Keywords

Apoptosis

Bibliometric analysis

Bladder cancer

Cell death mechanisms

Immunotherapy

Ferroptosis

Photodynamic therapy

1 Introduction

Bladder cancer (BC) constitutes the most frequent urogenital malignancy. GLOBOCAN 2022 reports BC as the ninth most common cancer worldwide and the thirteenth leading cause of cancer-related mortality, while epidemiological studies consistently demonstrate a 3–4-fold higher incidence in males compared to females [1]. Urothelial carcinoma (UC) constitutes the predominant histological subtype of bladder tumors. Histopathological classification is based on detrusor muscle invasion status: non-muscle-invasive bladder cancer (NMIBC) refers to tumors confined to the mucosal epithelium or lamina propria, whereas muscle-invasive bladder cancer (MIBC) denotes invasion into the muscularis propria layer [2]. Among these, NMIBC accounts for approximately 75% of BC cases, while MIBC comprises the remaining 25%. Studies report alarmingly high 5-year recurrence and progression rates for NMIBC—up to 78% and 45%, respectively—which complicate clinical management and elevate recurrence risks. For intermediate- to high-risk NMIBC, the cornerstone initial therapy involves transurethral resection of bladder tumor (TURBT) followed by adjuvant intravesical Bacillus Calmette-Guérin (BCG). Notably, BCG immunotherapy remains the only established, widely adopted conservative treatment proven to reduce progression risk in high-risk NMIBC [3–5]. Conversely, MIBC typically presents with high-grade histology, locally advanced disease, or metastases, necessitating cisplatin-based neoadjuvant chemotherapy and radical cystectomy, often supplemented by biomarker-guided immune checkpoint inhibitors or targeted combination therapies [6, 7]. Although current strategies (e.g., TURBT, radical cystectomy, chemotherapy, and immunotherapy) form the therapeutic backbone, persistent challenges include high recurrence rates and treatment resistance in advanced/metastatic BC. Consequently, elucidating pathogenic mechanisms and identifying actionable therapeutic targets through fundamental research is critically needed to improve clinical outcomes.

As a genitourinary malignancy, BC pathogenesis is closely linked to cell death mechanisms. Diverse forms of cell death—including apoptosis (regulated by factors such as Bcl-2 and survivin), pyroptosis, and ferroptosis—play critical roles in BC initiation, progression, and treatment response. Dysregulation of apoptosis-related gene expression is a well-established key factor in the development and advancement of numerous cancers [8]. Pyroptosis, identified as a distinct form of programmed cell death (PCD), demonstrates a close association with urothelial cell damage in BC development; consequently, several compounds can mitigate BC progression by inhibiting pyroptosis [9]. Compared to normal cells, tumor cells require increased iron for malignant proliferation, implying heightened tumor susceptibility to ferroptosis. Crucially, ferroptosis contributes significantly to BC pathogenesis and can induce death in apoptosis-resistant tumor cells[10]. Therefore, these cell death mechanisms are fundamentally implicated in BC. Although substantial clinical research on bladder cancer cell death has been documented and significant progress achieved, current studies remain fragmented. Critically, a systematic analysis delineating the fields developmental trajectory, core research foci, and emerging frontiers is lacking. To address this gap, we conducted a comprehensive bibliometric study.

Bibliometrics employs statistical methods to quantitatively analyze scholarly publications, systematically mapping research trajectories and intellectual landscapes. Through mathematical techniques, it elucidates academic contributions—including affiliations, journals, authors, citations, and keywords—while integrating data visualization to assess literature volume, quality, impact, and structural relationships [11, 12]. This approach provides an ideal framework for identifying influential research, emerging hotspots, and global trends, thereby generating actionable insights for future investigations. Applying this methodology, our study integrates statistical analysis with advanced visualization tools (e.g., co-citation networks, keyword clustering) to establish the first bibliometric overview of global research on cell death mechanisms in bladder cancer. We further identify evolving research trends and future directions. The findings provide researchers and clinicians with a definitive roadmap of the fields evolution and highlight priority areas for targeted exploration.

2 Data and Methods

2.1 Data source and retrieval strategy

The WoSCC, a premier multidisciplinary database indexing high-impact, peer-reviewed journals, was selected for this bibliometric analysis. Its rigorous curation ensures the inclusion of high-quality bladder cancer research, aligning with our objective to provide a reliable and comprehensive field assessment. On December 31, 2024, we systematically retrieved publications using the following search strategy: (Cell Death Terms): TS=("Cell Death" OR "Death, Cell" OR Apoptosis OR "Classical Apoptosis" OR "Classic Apoptosis" OR "Programmed Cell Death, Type I" OR "Extrinsic Pathway Apoptosis" OR "Intrinsic Pathway Apoptosis" OR "Programmed Cell Death" OR "Caspase-Dependent Apoptosis" OR Pyroptosis OR "Inflammatory Apoptosis" OR "Pyroptotic Cell Death" OR "Caspase-1 Dependent Cell Death" OR Necroptosis OR Ferroptosis OR Disulfidptosis) AND (Bladder Cancer Terms): TS=("bladder cancer" OR "Bladder Neoplasm" OR "Bladder Tumor" OR "Cancer of Bladder" OR "Urinary Bladder Cancer*"). Inclusion Criteria: English-language original research, reviews, experimental studies, and clinical trials. Exclusion Criteria: Conference abstracts, book chapters, and non-peer-reviewed publications. The initial search yielded 5,880 records. After duplicate removal using EndNote followed by manual verification, two independent authors screened titles/abstracts. Publications unrelated to bladder cancer cell death mechanisms were excluded. Discrepancies were resolved through discussion with a third author. This process resulted in 5,392 articles for final analysis (Fig. 1).

Fig. 1

Flowchart of literature search

2.2 Data analysis and visualization

This study employed GraphPad Prism, CiteSpace, and VOSviewer for comprehensive data analysis and visualization, focusing on annual publication counts, national/regional publication trends, proportional distributions, and the generation of scientific knowledge maps. Specifically, GraphPad Prism was utilized to calculate and visualize publication volumes by year, publication trends across regions/countries, and proportional research distributions. VOSviewer facilitated the analysis of collaborations among countries/regions, institutions, and authors, as well as keyword clustering. CiteSpace was employed to analyze citation bursts, keyword co-occurrence patterns, and cited reference networks, thereby identifying emerging research frontiers and intellectual bases within the field. In the resulting visualizations, each node represents an element (e.g., country, institution, keyword); node size corresponds to publication count (for countries/institutions) or keyword frequency, while connecting lines denote collaboration strength or keyword co-occurrence frequency, with colors differentiating clusters or temporal periods. Furthermore, CiteSpace enabled the examination of citation burst evolution and keyword emergence trends over time, thereby providing insights into the developmental trajectory of the research field.

3 Results

3.1 Global trend in publication outputs andcitations

Analysis of the WoSCC revealed a total of 5,392 publications on bladder cancer cell death indexed as of December 31, 2024. These publications originated from 654 institutions across 95 countries/regions, were published in 1,235 journals, and involved contributions from 1,693 authors. Annual publication trends are presented in Fig. 2. The field exhibited a consistent upward trajectory, with an average annual growth rate of 14.44% and a peak output of [specify number] publications in 2022. This trend signifies a substantial and progressive increase in global research activity focused on bladder cancer cell death. Furthermore, the pronounced acceleration in recent years strongly suggests that bladder cancer cell death will remain a prominent and actively investigated area with significant research potential in the foreseeable future.

Fig. 2

Annual volume of publications

3.2 Distribution of countries/regions

A total of 95 countries/regions have contributed to bladder cancer cell death research. Figures 3A and 3B illustrate the annual publication outputs of the top 10 productive countries/regions over the past decade. The top five contributors were China, the United States, Japan, Germany, and South Korea. China accounted for 45.38% of total publications, significantly exceeding the combined output of all other nations. Among the top 10 countries/regions, Chinese publications accumulated 62,119 citations (Table 1)—substantially higher than all others—with a citations-per-publication ratio of 25.39 (ranking 7th globally), indicating consistently high research quality. The United States ranked second in publications (1,093 papers), citations (54,042), and citations-per-publication ratio (49.45), reflecting strong citation influence. Notably, the United Kingdom, though ranking 7th in publications (152 papers), achieved the highest citations-per-publication ratio (53.63), demonstrating exceptional impact and scholarly quality. Both the collaborative network (Fig. 3C) and geospatial coordination map (Fig. 3D) underscore the dominant scholarly leadership of China and the United States, as their disproportionately large node sizes signify superior productivity and academic engagement in this field.

Fig. 3

(A). Line graph of national publications (B). Heat map of national publications (C). Networks of country cooperation (D). Knowledge visualization map for international collaboration

Table 1
Table of country published literature
Rank	Country/region	Article counts	centrality	Percentage (%)		Citation per publication
1	CHINA	2447	0.11	45.38%	62119	25.39
2	USA	1093	0.5	20.27%	54052	49.45
3	JAPAN	390	0.05	7.23%	14355	36.81
4	GERMANY	256	0.09	4.75%	8342	32.59
5	SOUTH KOREA	186	0.05	3.45%	5657	30.41
6	ITALY	165	0.06	3.06%	5420	32.85
7	ENGLAND	152	0.1	2.82%	8151	53.63
8	CANADA	120	0.08	2.23%	5100	42.50
9	INDIA	112	0.07	2.08%	2826	25.23
10	IRAN	108	0.07	2.00%	2436	22.56

3.3 Institutions

A total of 654 institutions have published research on bladder cancer cell death (Table 2; Fig. 4). All the 10 institutions by publication volume originated from China and the United States. The University of Texas System led with 178 publications (10,335 citations; average citation = 58.06), followed by UTMD Anderson Cancer Center (2nd; 123 publications, 6,967 citations; average citation = 56.64) and Nanjing Medical University (3rd; 122 publications, 3,689 citations; average citation = 30.02). Further analysis revealed a pronounced preference for intra-country collaboration among both domestic and international institutions. This observed bias highlights the need to strengthen global research partnerships and mitigate academic fragmentation.

Table 2
Table of Institutional Published Literature
Rank	Institution	Country	Number of studies	Total citations	Average citation
1	University of Texas System	USA	178	10335	58.06
2	UTMD Anderson Cancer Center	USA	123	6967	56.64
3	Nanjing Medical University	China	122	3689	30.24
4	Sun Yat Sen University	China	105	3426	32.63
5	Zhejiang University	China	99	3440	34.75
6	Shanghai Jiao Tong University	China	97	2311	23.82
7	Huazhong University of Science & Technology	China	97	2996	30.89
8	Peking University	China	96	2525	26.30
9	China Medical University	China	93	2205	23.71
10	University of California System	USA	91	5130	56.37

Fig. 4

Networks of institutional co-operation

3.4 Journals

Tables 3 and Fig. 4 list the top 10 journals by publication volume and co-citation frequency, respectively. The Journal of Urology led in productivity (106 publications, 1.97%), followed by Oncology Reports (100, 1.85%), Oncotarget (99, 1.84%), Oncology Letters (95, 1.76%), International Journal of Molecular Sciences (93, 1.72%), and PLOS ONE (86, 1.59%). Among these, Cancer Research had the highest impact factor (IF 12.5). Notably, 60% were JCR Q1 journals—a dominance attributable to the field's alignment with high-impact, rigorously peer-reviewed venues, reflecting the topic's translational significance and interdisciplinary nature. Journal influence was further assessed through co-citation analysis (Fig. 5B; Table 4). CANCER RESEARCH ranked first (3,405 co-citations), ahead of ONCOGENE (2,356) and CLINICAL CANCER RESEARCH (2,290). Nature, while 4th in co-citations (2,273), achieved the highest citation density (50.5 citations/article) among top journals. Eighty percent of co-cited journals belonged to JCR Q1, reinforcing their foundational role in the field's knowledge structure.

Table 3
Table of Journal Publications
Rank	Journal	Article counts	Percentage(5392)	IF	Quartile in category
1	journal of urology	106	1.97%	6.4	Q1
2	oncology reports	100	1.85%	3.4	Q2
3	oncotarget	99	1.84%	-	-
4	oncology letters	95	1.76%	2.5	Q3
5	international journal of molecular sciences	93	1.72%	4.9	Q1
6	plos one	86	1.59%	2.9	Q1
7	international journal of oncology	82	1.52%	4.5	Q1
8	cancer research	80	1.48%	12.5	Q1
9	cancers	74	1.37%	4.5	Q1
10	anticancer research	71	1.32%	1.6	Q4

Fig. 5

(A). Density map of journal publications (B). Co-citation network map of journals (C). dual map of journals

Table 4
Co-citation table of journals
Rank	Cited Journal	Co-Citation	IF(2024)	Quartile in category
1	CANCER RES	3405	12.5	Q1
2	ONCOGENE	2356	6.9	Q1
3	CLIN CANCER RES	2290	10.4	Q1
4	NATURE	2273	50.5	Q1
5	J BIOL CHEM	2084	4.0	Q2
6	CELL	2035	45.6	Q1
7	P NATL ACAD SCI USA	2002	9.4	Q1
8	INT J CANCER	1916	5.7	Q1
9	EUR UROL	1844	25.3	Q1
10	PLOS ONE	1798	2.9	Q1

The density visualization (Fig. 5A) revealed three research clusters: Core oncology: Cancer Research, British Journal of Cancer, International Journal of Cancer Clinical translation: Journal of Urology, Translational Andrology and Urology, Biomedicine & Pharmacotherapy. Basic mechanisms: Journal of Biological Chemistry, Journal of Cellular Biochemistry, Frontiers in Genetics. Dual-map overlay (Fig. 5C) traced citation pathways, identifying three key knowledge flows: Yellow trajectory: Publications in Molecular/Biology/Immunology journals influence both basic science (Molecular/Biology/Immunology) and clinical (Health/Nursing/Medicine) domains. Green trajectory: Medicine/Medical Clinical research draws significantly from Health/Nursing/Medicine insights. This topology indicates an evolving research front (left clusters) and established knowledge base (right clusters), predicting future diversification from molecular mechanisms toward clinical and translational oncology.

Dual-map overlay analysis (Fig. 5C) identified three citation trajectories: Yellow: Molecular/biology/immunology research influencing both its own domain and health/nursing/medicine; Green: Medicine/clinical publications informed by health/nursing/medicine insights; Predicted shift: Emerging focus from molecular/biology/immunology toward clinical applications. Collectively, these trajectories indicate evolving research fronts in bladder cancer cell death mechanisms."

3.5 Authors

Table 5 lists the top 10 most prolific authors in bladder cancer cell death research. Collectively, these authors contributed 273 publications (5.06% of total publications). Kim Wun-Jae led with 37 papers, followed by Liu Yu-Chen and Zhang Wei (33 papers), Choi Yung-Hyun (29 papers), and Chen Wei (25 papers).CiteSpace co-authorship analysis (Fig. 6A) revealed distinct research clusters led by prominent authors (e.g., Kim wun-jae, Zhang wei, Liu yuchen), while peripheral contributors exhibited limited collaborative engagement, suggesting more independent research trajectories. Figure 6B and Table 5 further identify the top 10 co-cited and cited authors. The co-citation network’s largest nodes represent the most influential scholars: Jemal a (446 co-citations), Siegel rl. (441), Wang Y. (316), Witjes Ja (315), and Babjuk m (305).

Table 5
Author's publications and co-citation table
Rank	Author	Count	Rank	Co-cited author	Citation
1	Kim, wun-jae	37	1	Jemal a	446
2	Liu, yuchen	33	2	Siegel rl	441
3	Zhang, wei	33	3	Wang y	316
4	Choi, yung hyun	29	4	Witjes ja	315
5	Chen, wei	25	5	Babjuk m	305
6	Huang, weiren	25	6	Bellmunt j	303
7	Cai, zhiming	24	7	Kamat am	281
8	Moon, sung-kwon	23	8	Antoni s	267
9	He, dalin	22	9	Li j	247
10	Schulz, wolfgang a.	22	10	Sung h	243

Fig. 6

(A). Cooperation network of authors (B). Co-citation network of authors

3.6 Citation and co-citation analysis

Citation analysis serves as a critical method for assessing scholarly impact, reflecting both a publication's influence within a field and prevailing research trends. Table 6 lists the top 10 most-cited papers in bladder cancer cell death research. The highest-cited publication, 'Comprehensive molecular characterization of urothelial bladder carcinoma' (110 citations), established foundational molecular frameworks for bladder cancer cell death. This was followed by 'Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma' (103 citations), which advanced systemic therapy approaches, and 'Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma...' (79 citations), which validated immune checkpoint inhibition efficacy. Collectively, these seminal works provide conceptual foundations for modern bladder cancer cell death research [13, 15].

Table 6
Co-citation table of literature
Rank	Title	Journal	author(s)	Total citations
1	Comprehensive molecular characterization of urothelial bladder carcinoma	NATURE	Weinstein JN	110
2	Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma	NEW ENGL J MED	Bellmunt J	103
3	Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial	LANCET	Rosenberg JE	79
4	Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer	CELL	Robertson AG	79
5	Advances in bladder cancer biology and therapy	NAT REV CANCER	Tran LD	78
6	Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial	LANCET ONCOL	Sharma P	66
7	Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial	LANCET	Balar AV	66
8	Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity	NAT REV CANCER	Knowles MA	60
9	MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer	NATURE	Powles T	50
10	Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial	LANCET	Powles T	49

To elucidate intellectual relationships within the citation landscape, we performed co-citation clustering analysis on 5,392 publications (1991–2024) using time-slicing. This generated a comprehensive co-citation network (Fig. 7A) comprising 2,046 nodes and 8,431 links (density = 0.004). The analysis identified 19 distinct clusters (Figs. 7B and 7C), ranked by size from largest (0) to smallest (19). The network demonstrated exceptional structural validity, with high modularity (Q = 0.8388) and mean silhouette score (S = 0.8817), confirming robust cluster homogeneity.These co-citation clusters represent the intellectual foundation of bladder cancer cell death research. We synthesized five major research hotspots from the 19 clusters: (1) Cell Death Mechanisms & Molecular Regulation: 0 Ferroptosis, 1 Bcl-2, 2 Survivin; (2) Bladder Cancer Phenotypes: 3 Urothelial carcinoma, 16 Bladder cancer transformation; (3) Therapeutic Interventions: 4 Proliferation pathways, 7 Ursolic acid, 11 Metformin, 9 Allyl isothiocyanate. (4) Biomarkers & Diagnostics: 8 Tumor markers, 5 lncRNAs, 6 miRNAs, 12 Circular RNAs. (5) Clinical Translation: 10 Animal models, 13 Clusterin, 14 FAS-ligand, 17 Clinical implications, 18 ROS signaling.

Fig. 7

(A). co-cited network of literature (B). Clustering of co-cited literature (C). Peak map of co-cited literature (D). Bursting map of cited literature

Citation burst analysis reveals rapidly evolving research frontiers. Figure 7D identifies the top 50 references with the strongest citation bursts. The earliest significant burst (2007) emerged from seminal work by Jemal et al., which highlighted bladder cancer mortality rates and galvanized research interest in therapeutic development. The most intense burst (strength = 85.61) was observed for Sung et al.'s 2021 CA: A Cancer Journal for Clinicians study, persisting through 2024.Current citation bursts (initiated 2022 and ongoing) are driven by five influential publications: Sung H, et al. (2021) CA Cancer J Clin [16], Lenis AT, et al. (2020) JAMA[17], Patel VG, et al. (2020) CA Cancer J Clin [18], Tran L, et al. (2020) Nature [19], Dobruch J, et al. (2021) Medicina (Kaunas) [20]. Collectively, these bursting publications—dominated by epidemiological updates and clinical guideline revisions—demonstrate the field's dynamic evolution toward translational applications.

3.7

Keywords

Keywords encapsulate core research concepts, and their co-occurrence analysis reveals both disciplinary hotspots and emerging trends. Using VOSviewer, we constructed a keyword co-occurrence network from 5,392 publications (Table 7; Figs. 8A and 8B). The most frequent terms were apoptosis (2,299 occurrences), bladder cancer (2,045), proliferation (797), growth (570), and activation (500).Network clustering identified five thematic domains: Cell Death Mechanisms (Green): apoptosis, autophagy, mitochondrial dysfunction, ROS; Tumor Progression (Blue): bladder cancer, proliferation, migration, metastasis; Clinical Therapeutics (Red): chemotherapy, targeted therapy, doxorubicin, cisplatin, PD-1/PD-L1 inhibition; Molecular Biomarkers (Yellow): p53, biomarkers; Disease Subtyping (Purple): urothelial carcinoma.

Table 7
High Frequency Keyword Table
Rank	Keyword	Counts	Rank	Keyword	Counts
1	apoptosis	2299	11	therapy	334
2	bladder cancer	2045	12	cisplatin	327
3	proliferation	797	13	urothelial carcinoma	309
4	growth	570	14	migration	303
5	activation	500	15	pathway	285
6	invasion	445	16	p53	283
7	progression	439	17	prognosis	280
8	metastasis	415	18	immunotherapy	278
9	inhibition	384	19	resistance	278
10	chemotherapy	364	20	survival	274

Fig. 8

(A). Network map of high-frequency keywords (B). Density map of keywords (C). Peak map of keyword clustering (D). clustering map of keywords

Using CiteSpace, we generated timeline visualizations (Figs. 8C and 8D) to illustrate the temporal evolution of research hotspots. Our analysis identified lncRNA, bladder cancer, apoptosis, tumor growth, photodynamic therapy, in vivo studies, identification, and tissue analysis as current predominant research foci. Furthermore, we performed keyword burst analysis via CiteSpace, selecting the top 50 terms with the strongest citation bursts during 1991–2024, ranked by burst intensity (Fig. 9). These terms represent the field's current research priorities and potential future directions. Notably, "invasion" exhibited the highest burst strength. Given that invasion underpins the entire progression, metastasis, and prognosis of bladder cancer, it constitutes a key entry point for understanding malignant behavior and optimizing diagnosis/therapy. Additionally, keywords including "pembrolizumab", "multicenter" trials, "metabolism", the "tumor microenvironment", "cell death" mechanisms, and "long noncoding RNA" (lncRNA) continued to demonstrate significant burst strength in 2024, strongly suggesting these areas will likely remain central to future research.

Fig. 9

Bursting map of keywords

4 Discussion

4.1 General information

A comprehensive search of the WoSCC database (1991–2024) identified 5,392 publications on bladder cancer cell death mechanisms, contributed by 1,693 authors from 654 institutions across 95 countries/regions and published in 1,235 journals. Despite intermittent fluctuations, annual publication output exhibited an overall upward trajectory (Fig. 2). Notably, a sharp surge occurred after 2016, peaking significantly in 2017. Citation burst analysis (Fig. 7D) attributed this peak to increased research focus on programmed cell death-based chemotherapy for bladder cancer patients beginning in 2017. Specifically, 7 of the top 50 references with the strongest citation bursts were published in 2017, including 3 directly addressing chemotherapy. Leading contributors Balar AV, Sharma P, and Bellmunt J investigated chemotherapy regimens targeting programmed cell death (using agents including atezolizumab, pembrolizumab, and nivolumab), thereby establishing the foundation for subsequent research on cell death mechanism-based immunotherapy combinations in bladder cancer [21, 23]. Concurrently, geographic collaboration networks revealed the top 10 contributing countries spanning three regions: Asia, Europe, and North America. Of these, China emerged as a dominant contributor, ranking among the top three in both publication volume and citation frequency. The sustained increase in annual publications and citation frequency since 1991 reflects intensifying global interest in bladder cancer cell death research, underscoring its growing academic significance and translational potential.

An in-depth analysis of contributions from 95 countries/regions revealed a heterogeneous global research landscape. China emerged as the dominant contributor in bladder cancer cell death research, evidenced by its leading publication output (2,447 papers, 45.38% of total) and high citation frequency (62,199 citations). Notably, China is not only the sole developing nation among the top 10 contributing countries but has also demonstrated exponential publication growth since 2011, establishing a significant lead over other nations. While China dominates in research volume, the United States and United Kingdom lead in citation impact (mean citations: 49.45 and 53.63, respectively), reflecting higher-quality contributions. This disparity underscores the critical need for enhanced international collaboration to simultaneously augment the volume and quality of global research output [24].

Institutional contributions reflect distinct national research trajectories in this field. Notably, 7 of the top 10 institutions by publication volume are in China, while the remaining 3 are in the United States. Among these, the University of Texas System, UTMD Anderson Cancer Center, and Nanjing Medical University lead bladder cancer cell death mechanism research, contributing substantially to global output. Critically, Chinese institutions comprise 70% of the top 10 contributors and account for 45.38% of total publications, underscoring their dominant quantitative role. Conversely, U.S. institutions exhibit significantly higher per-publication citation rates (49.45 vs. China’s 25.39), reflecting greater emphasis on high-impact research. Furthermore, the three most-cited institutions—University of Texas System (10,335 citations), UT MD Anderson Cancer Center (6,967), and University of California System (5,130)—far surpass leading Chinese institutions (e.g., Nanjing Medical University: 3,689; Sun Yat-sen University: 3,426). This citation disparity may stem from language barriers, data-sharing policies, and divergent research priorities. Specifically, U.S. institutions (e.g., University of Texas System) maintain broader international collaborations, publishing predominantly in high-impact English journals; in contrast, Chinese institutions focus on domestic networks, indicating opportunities for enhanced global engagement. To address these gaps, prioritized strategies include: (1) establishing multinational consortia for data sharing; (2) developing open-data platforms compliant with privacy regulations; and (3) overcoming language barriers via professional translation services and standardized English scientific reporting. Implementing these measures will amplify global impact and accelerate clinical translation of bladder cancer cell death research.

Influential authors including Jemal A, Bellmunt J, Witjes JA, and Siegel RL have profoundly shaped this field through their work on bladder cancer epidemiology, cell death mechanisms, and therapeutic applications. Notably, Bellmunt J pioneered research on programmed cell death-based therapies for BC [22], establishing him as a key opinion leader. Concurrently, Witjes JA's clinical studies on NMIBC treatment [25] directly informed subsequent clinical decisions regarding cell death mechanism-immunotherapy synergies. These contributions underscore the critical role of foundational research in driving therapeutic innovation. Regarding dissemination, Journal of Urology, Oncology Reports, and Oncotarget led in publication volume for bladder cancer cell death research. However, citation impact was dominated by high-impact journals: CANCER RESEARCH (IF = 12.5; co-citations: 3,405), NATURE (IF = 50.5; co-citations: 2,273), and CELL (IF = 45.6; co-citations: 2,035). Strikingly, 90% of the top 10 co-cited journals (e.g., European Urology, ONCOGENE) are JCR Q1 publications, emphasizing the field's academic significance. Coupling analysis further revealed that key findings are primarily published in immunology, molecular biology, and genetics journals. Cross-disciplinary integration of fundamental sciences—particularly molecular biology, genetics, biomaterials, and medicinal chemistry—provides the essential framework for elucidating cell death mechanisms and translating discoveries into clinical applications. Consequently, multidisciplinary collaboration across these domains is poised to accelerate therapeutic optimization and advance precision medicine for bladder cancer patients.

4.2 Frontiers

Co-citation networks mapped via CiteSpace and VOSviewer reveal distinct thematic clusters representing major research foci in bladder cancer cell death (Fig. 8). These span a multidimensional continuum from fundamental mechanisms to clinical translation, with hotspots concentrated in: Cell death mechanisms (apoptosis, autophagy, mitochondrial dysfunction, ROS signaling); Tumor progression (bladder carcinogenesis, proliferation, migration, metastasis); Clinical strategies (chemotherapy, targeted therapy, immunohistochemical biomarkers). Critically, immunotherapy has emerged as a dominant clinical paradigm. Contemporary trials position immune-based therapies as transformative interventions—specifically through their capacity to reprogram the tumor microenvironment (TME)—and dominate treatment research by leveraging cell death pathways for antitumor efficacy [26, 27]. This predominance underscores the therapeutic imperative of cell death mechanism-based immunotherapy in bladder cancer.

PCD mechanisms—including apoptosis and ferroptosis—represent a critical research frontier in bladder oncology, profoundly influencing tumorigenesis, progression, prognostic prediction, and therapeutic interventions[28–30]. Therefore, current research focuses on multi-faceted breakthroughs targeting these core mechanisms. Specifically, in targeted drug delivery, nanoparticle-based systems demonstrate substantial potential for overcoming traditional therapeutic limitations [31, 32]. These systems enhance solubility, tumor permeability, and targeting specificity of PCD-inducing agents, thereby reducing required dosages and systemic toxicity while precisely augmenting tumor cell death induction, which improves therapeutic precision and efficacy. Concurrently, the TME receives considerable attention due to its pivotal regulatory role in PCD. Complex TME interactions—such as immunosuppression and therapy resistance induction—coupled with its secreted growth factors, cytokines, and chemokines, not only support tumor growth and metastasis but also significantly impair therapeutic PCD induction. Consequently, elucidating and modulating TME-mediated PCD regulation emerges as the key strategy to overcome treatment resistance[33].

Co-citation analysis of research trends highlights the evolving focus bladder cancer cell death mechanisms. Initially, early studies emphasized fundamental roles of cell death, demonstrating that tumor suppressor p53 critically regulates cell cycle progression and apoptosis under cytotoxic conditions [34, 35]. Subsequently, mid-phase research explored therapeutic applications, revealing synergistic effects between chemotherapy/radiotherapy and cell death pathways. Chemotherapeutic agents were confirmed to eliminate bladder cancer cells via apoptosis; unfortunately, tumor cells frequently developed chemoresistance. Consequently, researchers adopted combination strategies—such as chemo-radiotherapy—to induce cell death through complementary mechanisms, significantly enhancing treatment efficacy [36, 37]. Recently, investigations shifted toward precision medicine, integrating immunotherapy and PDT with cell death mechanisms [38, 39]. Collectively, this progression reflects the fields dynamism and its continuous advancement toward technologically driven clinical solutions.

4.2.1 Cell Death Mechanisms in Bladder Cancer: an in-depth exploration of bladder cancer

PCD constitutes an active cellular demise process triggered by specific signals to maintain internal homeostasis. Major PCD modalities include ferroptosis, apoptosis, cuproptosis, necroptosis, autophagy, and pyroptosis [40, 41]. Notably, apoptosis and ferroptosis represent critical anti-cancer mechanisms. Bladder cancer cells frequently evade elimination by acquiring apoptosis resistance, enabling survival, proliferation, and metastasis. Thus, apoptosis evasion constitutes a major therapeutic challenge. Critically, studies confirm that Survivin, a pivotal anti-apoptotic protein, directly mediates chemoresistance in bladder cancer. Therapeutic suppression of Survivin expression significantly enhances treatment efficacy while potently reducing chemoresistance development in preclinical models [42–44]. Furthermore, the B-cell lymphoma 2 (BCL-2) gene encodes a mitochondrial protein that regulates apoptotic PCD [45], while tumor suppressor p53 aberrantly influences bladder cancer chemoresistance through apoptosis induction [46]. Collectively, these dysregulated factors (Survivin, BCL-2, p53) not only drive tumor progression but also serve as poor prognostic indicators [47]. Consequently, targeting apoptotic pathways emerges as a promising clinical strategy for overcoming drug resistance, particularly in advanced or refractory bladder cancer.

Ferroptosis—an iron-dependent, lipid peroxidation-driven form of regulated cell death—is closely associated with bladder cancer progression [48]. Mechanistically, intracellular labile iron (Fe²⁺) catalyzes ROS generation via the Fenton reaction, oxidizing polyunsaturated fatty acids (PUFAs) in cell membranes. This initiates lipid peroxidation cascades, increasing membrane fragility and triggering cell demise. Moreover, impaired glutathione peroxidase 4 (GPX4) activity—a key antioxidant enzyme in the glutathione system—reduces antioxidant capacity, leading to lethal ROS accumulation [49, 50]. Research indicates that expression levels of ferroptosis suppressor genes, such as GPX4 and SLC7A11, are negatively correlated with tumor malignancy in bladder cancer tissue. Erastin is a classic ferroptosis inducer that inhibits the activity of the key intracellular transporter SLC7A11, thereby significantly reducing the cell's glutathione (GSH) synthesis capacity, triggering lipid peroxidation and ultimately leading to ferroptosis [51, 53]. Given ferroptosis plays a critical role in bladder cancer initiation, progression, and therapeutic resistance, its induction has emerged as a promising strategy to trigger cancer cell death, particularly in aggressive malignancies resistant to conventional therapies [54]. Therefore, therapeutic strategies targeting ferroptosis offer novel avenues for precision medicine in bladder cancer.

Substances released during apoptosis and ferroptosis can profoundly alter the composition and function of the TME. Specifically, when ferroptosis occurs in bladder cancer cells, it releases damage-associated molecular patterns (DAMPs), including ATP, high-mobility group box 1 (HMGB1), calreticulin (CRT), and pro-inflammatory cytokines. Notably, HMGB1 can bind receptors on dendritic cells (DCs) within the TME, promoting DC maturation. Mature DCs efficiently engulf, process, and present tumor antigens, thereby facilitating T cell priming and ultimately enhancing tumor cell killing while inhibiting tumor growth [55, 56]. In contrast, apoptotic cells also release diverse signaling molecules that influence the TME. Apoptotic signaling may affect intratumoral cell competition by stimulating proliferation of neighboring cells and exerting paracrine effects. Furthermore, apoptosis promotes the recruitment of immunosuppressive cells—such as regulatory T cells (Tregs), M2-polarized macrophages, and myeloid-derived suppressor cells (MDSCs)—which can contribute to cancer progression and therapy resistance [57]. Collectively, these findings demonstrate that ferroptosis, apoptosis, and the TME are not isolated entities in bladder cancer pathogenesis. Instead, they interact through intricate molecular mechanisms to co-regulate tumor initiation, progression, metastasis, and therapeutic responses, forming a dynamic, interconnected regulatory network.

4.2.2 Clinical Translation of Cell Death Mechanisms

Translating cell death mechanisms into clinical strategies represents a promising frontier in BC treatment. BC, characterized by high mutational burden, is particularly amenable to immunotherapy, especially checkpoint inhibitors targeting PD-1 or its ligand PD-L1. The interaction between programmed death-ligand 1 (PD-L1) on tumor cells and programmed cell death protein 1 (PD-1) on immune cells critically enables tumor immune evasion. Blocking this interaction with immune checkpoint inhibitors (ICIs) provides a potent strategy for targeted cancer immunotherapy [58, 59]. Notably, both apoptosis and ferroptosis—when accompanied by intact damage-associated molecular pattern (DAMP) release—can trigger robust immunogenicity. Chemotherapy-induced immunogenic cell death (ICD), which involves DAMP release (e.g., calreticulin, ATP, HMGB1), exemplifies this synergy and enhances immune activation when combined with ICIs [60]. Consequently, combining ferroptosis inducers with ICIs demonstrates synergistic efficacy by enhancing anti-tumor immunity and overcoming immune evasion. Simultaneously, PDT has emerged as an attractive modality in cancer treatment. PDT induces apoptosis or necrosis primarily through ROS-mediated damage to cellular components (e.g., proteins, lipids, nucleic acids) [61]. Crucially, for NMIBC—which predominantly affects the bladder mucosa—intravesical PDT enables precise targeting. Following instillation of a photosensitizer, laser activation at tumor-specific wavelengths selectively eradicates mucosal lesions while minimizing damage to the muscularis propria and urethra, thereby reducing recurrence rates [62]. Importantly, PDT-generated ROS concurrently trigger multiple cell death pathways: high-concentration ROS directly disrupt mitochondrial membranes to initiate apoptosis, while lipid membrane oxidation induces ferroptosis [63, 64]. Collectively, treatment strategies integrating cell death mechanisms (e.g., with IT or PDT) are gaining significant traction in BC management, creating novel therapeutic possibilities.

4.3 Limitations

This study employed bibliometric methods to analyze global research trends and emerging frontiers in bladder cancer cell death mechanisms. Notably, several limitations should be acknowledged. First, our analysis relied exclusively on English-language articles and reviews retrieved from WoSCC. This single-database approach may exclude relevant studies indexed in other databases (e.g., Scopus, PubMed) or published in other languages, potentially limiting the comprehensiveness of our findings. Future studies should integrate data from multiple databases to ensure more comprehensive coverage. Second, publication timelines inherently affect citation metrics; consequently, recent high-impact publications may be underrepresented due to their lower cumulative citation counts. Furthermore, our analysis did not distinguish between bladder cancer subtypes—such as urothelial carcinoma UC and non-urothelial carcinoma—or between MIBC and NMIBC. This broad categorization may obscure subtype-specific research trends. Although these limitations exist, the trends and insights elucidated in this study establish a solid foundation for understanding the current research landscape and guiding future investigations in this rapidly evolving field.

5 Conclusion

This bibliometric analysis comprehensively delineates the research landscape of bladder cancer cell death mechanisms from 1991 to 2024, identifying global trends, collaborative networks, and emerging frontiers. Key research foci include apoptosis regulation, ferroptosis pathways, immunotherapy applications, photodynamic therapy, and nanomedicine integration. Critically, our findings underscore the pivotal role of targeting cell death mechanisms to overcome therapy resistance and advance precision oncology in bladder cancer. Future investigations should prioritize exploring the interaction between cell death pathways and the tumor microenvironment, deciphering resistance mechanisms, and formulating targeted therapeutic strategies. These directions are pivotal for driving advancements in bladder cancer treatment and improving patient outcomes. Although constrained by acknowledged limitations, this study provides valuable insights into the evolving research trajectory and translational potential of targeting cell death mechanisms for bladder cancer management.

Abbreviation

WoSCC

Web of Science Core Collection

immunotherapy

PDT

photodynamic therapy

Bladder cancer

Urothelial carcinoma

NMIBC

non-muscle-invasive bladder cancer

MIBC

muscle-invasive bladder cancer

TURBT

transurethral resection of bladder tumor

BCG

Bacillus Calmette-Guérin

PCD

programmed cell death

TME

tumor microenvironment

BCL-2

B-cell lymphoma 2

PUFAs

polyunsaturated fatty acids

GPX4

glutathione peroxidase 4

GSH

glutathione

DAMPs

damage-associated molecular patterns

HMGB1

high-mobility group box 1

DCs

dendritic cells

Tregs

T cells

MDSCs

myeloid-derived suppressor cells

PD-L1

programmed death-ligand 1

PD-1

programmed cell death protein 1

ICIs

immune checkpoint inhibitors

DAMP

damage-associated molecular pattern

ICD

immunogenic cell death

ROS

reactive oxygen species

Declarations

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. Key Research and Development Program of Ningxia Hui Autonomous Region (2022BEG03133); Science and Technology Benefiting the People Project of Ningxia Hui Autonomous Region (2024CMG03004); Natural Science Foundation Project of Ningxia (2023AAC02076); Science and Technology Benefiting the People Project of Ningxia Hui Autonomous Region (2022CMG03030).

Ethics, Consent to Participate, and Consent to Publish declarations: not applicable.

Author Contribution

Z.C.: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft.Y.C: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft.N.F.: Writing – original draft, Writing – review & editing. F.F: Formal analysis, Investigation, Methodology, Resources, Software, Writing – review & editing. S.S: Formal analysis, Investigation, Methodology, Resources, Software, Writing – review & editing. H.W: Formal analysis, Investigation, Methodology, Resources, Software, Writing – review & editing. C.X: Funding acquisition, Project administration, Supervision, Writing – review & editing.

Data Availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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