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
10.1093/pcmedi/pbag012
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