image: JS-K inhibits bladder tumor growth in vivo. (A) Significant decrease in relative tumor volume (RTV) after JS-K treatment from 26 days. (B) HE staining of tumor tissue of WT and LC3B−/− mice after JS-K treatment. (C) LC3B expression was low in saline-treated UM-UC-3 tumors but significantly increased following JS-K treatment. Induction of LC3B by JS-K was weaker in LC3B-deficient tumors. (D) GPX4 was highly expressed in saline-treated tumors and significantly downregulated after JS-K treatment in both UM-UC-3 and LC3B-deficient tumors. The reduction was greater in WT tumors. (E) xCT expression was high under saline conditions but decreased significantly with JS-K treatment. The reduction was more pronounced in WT tumors than in LC3B-deficient tumors. (F) p62 levels were elevated in LC3B-deficient tumors under saline conditions, consistent with impaired autophagic flux. JS-K treatment reduced p62 expression in both WT and LC3B-deficient tumors, with a greater decrease observed in UM-UC-3 tumors. Two-way analysis of variance (ANOVA) testing with a P-value threshold of 0.05, followed by Tukey’s post-hoc testing with adjustment for multiple comparisons when indicated. ***P < 0.001, ****P < 0.0001. Data are presented as the mean ± standard deviation (SD), n = 3.
Credit: Precision Clinical Medicine
Bladder cancer remains difficult to treat once it becomes advanced, recurrent, or resistant to conventional therapies. A new study identifies a promising vulnerability in bladder cancer cells: the tight connection between autophagy, the cell’s recycling system, and ferroptosis, an iron-dependent form of regulated cell death. The researchers found that JS-K, a nitric oxide (NO)-releasing prodrug, can push bladder cancer cells toward ferroptosis by damaging mitochondria, disturbing iron balance, increasing oxidative stress, and weakening key survival defenses. By combining cell experiments, animal models, and patient-data analyses, the study provides a clearer mechanistic basis for exploiting iron-driven cancer cell death.
Bladder cancer is one of the most common urological cancers, and treatment remains challenging for patients with advanced disease. Surgery, intravesical therapy, chemotherapy, and targeted drugs have improved care, but recurrence, toxicity, and therapy resistance continue to limit long-term control. Ferroptosis has attracted growing interest because it kills cells through iron overload, lipid peroxidation, and reactive oxygen species (ROS), mechanisms that may bypass some conventional resistance pathways. Yet the role of autophagy in shaping ferroptosis in bladder cancer has remained incompletely understood. Due to these challenges, deeper investigation is needed into therapies that can exploit iron-dependent tumor cell death and its upstream regulatory mechanisms.
A research team from The First Affiliated Hospital of Jinan University, Affiliated Hospital of Guangdong Medical University, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Macau University of Science and Technology, the University of Dundee, and the Macau Institute for Artificial Intelligence in Medicine reported (DOI: 10.1093/pcmedi/pbag012) the findings in Precision Clinical Medicine on 25 April 2026. The study examined how JS-K suppresses bladder cancer progression and whether autophagy helps drive ferroptosis, using T24 and UM-UC-3 bladder cancer cells, a BALB/c nude mouse xenograft model, bulk RNA sequencing, and single-cell RNA sequencing (scRNA-seq).
The researchers first showed that JS-K produced several hallmarks of ferroptosis in bladder cancer cells, including mitochondrial shrinkage, lipid peroxidation, ROS accumulation, and intracellular iron overload. These changes were accompanied by reduced levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), two proteins that normally protect cells from ferroptotic damage. When LC3B-mediated autophagy was inhibited or knocked down, JS-K-induced iron accumulation, malondialdehyde (MDA) production, ROS elevation, and cell death were weakened, indicating that autophagy acts upstream of ferroptosis. In mouse xenograft models, JS-K significantly suppressed tumor growth, but this antitumor effect was reduced when LC3B was silenced. Integrated transcriptomic and scRNA-seq analyses further linked LC3B with ferroptosis-related genes, including CISD1 and NCOA4, and identified CISD1 as a prognostically relevant ferroptosis marker in bladder cancer.
The authors said the study highlights a cancer-killing route that may be especially relevant for tumors that resist standard treatment. They said JS-K appears to expose a metabolic weakness in bladder cancer cells by amplifying oxidative stress, disturbing iron handling, and lowering ferroptosis defenses. Rather than viewing autophagy and ferroptosis as separate processes, the work suggests that their interaction can become a therapeutic lever. The authors said this mechanistic insight provides a foundation for further preclinical development of JS-K and for identifying tumor states that may be more responsive to autophagy–ferroptosis-based strategies.
The findings may support the development of new bladder cancer therapies that act through iron-dependent tumor cell death. By identifying LC3B-mediated autophagy as a driver of JS-K-induced ferroptosis, the study provides a potential biomarker-guided direction for future drug testing. The links among LC3B, ferroptosis-related genes, patient prognosis, and immune-cell patterns also suggest that this pathway may influence not only tumor survival but also the tumor immune microenvironment. Although JS-K remains an experimental anticancer agent and requires further pharmacokinetic, toxicology, and translational evaluation, the work strengthens the case for targeting the autophagy–ferroptosis axis in bladder cancer.
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References
DOI
Original Source URL
https://doi.org/10.1093/pcmedi/pbag012
Funding Information
This work was supported by the Guangdong Medical Science and Technology Research Fund Project (No.A2022146), the National Natural Science Funds (No. 81272833) of China and the Fundo para o Desenvolvimento das Ciências e da Tecnologia (FDCT FDCT 0055/2022/A1 and 0022/2025/RIA1).
About Precision Clinical Medicine
Precision Clinical Medicine (PCM) commits itself to the combination of precision medical research and clinical application. PCM is an international, peer-reviewed, open-access journal that publishes original research articles, reviews, clinical trials, methodologies, opinions in the field of precision medicine in a timely manner. By doing so, the journal aims to provide new theories, methods, and evidence for disease diagnosis, treatment, prevention and prognosis, so as to establish a communication platform for clinicians and researchers that will impact practice of medicine. The journal covers all aspects of precision medicine, which uses novel means of diagnosis, treatment and prevention tailored to the needs of a patient or a sub-group of patients based on the specific genetic, phenotypic, or psychosocial characteristics. Clinical conditions include cancer, infectious disease, inherited diseases, complex diseases, rare diseases, etc. The journal is now indexed in ESCI, Scopus, PubMed Central, etc., with an impact factor of 5.0 (JCR2024, Q1). For further information, please refer to the journal homepage: https://academic.oup.com/pcm
Journal
Precision Clinical Medicine
Subject of Research
Not applicable
Article Title
JS-K induces autophagy-dependent ferroptosis in bladder cancer: a multimodal mechanistic and translational study
Article Publication Date
25-Apr-2026
COI Statement
The authors declare that they have no competing interests.