Objective: To investigate the inhibitory effect of the natural polyphenol Agrimol B on pancreatic ductal adenocarcinoma (PDAC) and its underlying molecular mechanisms.
Methods: The effects of Agrimol B on PDAC cell proliferation and apoptosis were assessed using Cell Counting Kit-8, colony formation, and flow cytometry assays. An in vivo PDAC xenograft mouse model was established for evaluation. Label-free quantitative proteomics, western blotting, immunofluorescence, and transmission electron microscopy were employed to analyze mitochondrial function, autophagy, and related signaling pathways. A patient-derived organoid model was used to evaluate the synergistic effects of Agrimol B with first-line chemotherapy drugs.
Results: Agrimol B significantly inhibited PDAC growth and induced apoptosis both in vitro and in vivo. Mechanistically, Agrimol B downregulated the expression of mitochondrial transcription termination factor 3, and promoted the accumulation of PTEN induced kinase 1 (PINK1) in mitochondria and Parkin translocation, thereby excessively activating PINK1/Parkin-dependent mitophagy. Concurrently, Agrimol B blocked lysosome biogenesis, leading to autophagosome accumulation and impaired autophagic flux. This dysfunctional autophagy ultimately mediated the anti-PDAC effect of Agrimol B. Furthermore, in PDAC patient-derived organoids, Agrimol B exhibited synergistic effects with first-line chemotherapy drugs such as gemcitabine and nab-paclitaxel.
Conclusion: Agrimol B exerts its anti-PDAC effects by downregulating mitochondrial transcription termination factor 3, hyperactivating PINK1/Parkin-mediated mitophagy, and obstructing autophagic flux. Its synergistic effect with chemotherapy drugs provides experimental evidence supporting its potential clinical translation.
Atherosclerosis is a disease centered on chronic inflammation, in which mitochondrial damage plays a key role in its initiation and progression. Traditionally, atherosclerosis is thought to be triggered by cholesterol accumulation, but recent studies have revealed that mitochondrial dysfunction has emerged as an important driving factor by inducing innate immune imbalance. In atherosclerosis, mitochondria undergo changes in membrane permeability, metabolic disorders, and dynamic imbalance due to oxidative stress and other factors, releasing mitochondrial damage-associated molecular patterns (mt-DAMPs). These mt-DAMPs activate innate immune pathways, promote the production of type I interferons and the release of pro-inflammatory factors such as interleukin 1β, and accelerate plaque progression. Mitophagy exerts a protective effect by eliminating damaged mitochondria. Specifically, the PINK1-Parkin pathway labels damaged mitochondria through ubiquitination; mitophagy receptors (such as NIX, FUNDC1, and BNIP3) directly bind to LC3 to initiate ubiquitination-independent mitophagy; and mitochondrial-derived vesicles selectively encapsulate damaged components and target them to lysosomes for degradation. All these processes can reduce mt-DAMP-induced damage and inhibit excessive immune activation. In this review, we summarize that innate immune imbalance caused by mitochondrial damage is a key mechanism for atherosclerosis progression. Mitochondrial quality control clears damaged mitochondria through multiple pathways, alleviates inflammatory responses and plaque burden, and provides potential targets for atherosclerosis treatment. Its precise regulatory mechanisms and drug development are future research directions.
Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs characterized by a covalently closed-loop structure. Although initially regarded as splicing byproducts, circRNAs are now recognized as essential regulators of gene and protein expression and play important roles in various human diseases. In recent years, growing evidence has indicated that a subset of circRNAs can be translated through cap-independent mechanisms to produce bioactive peptides or proteins. These findings expand the functional scope of circRNAs and offer new opportunities for RNA therapy. This review summarizes recent advances in circRNA biology, with an emphasis on their potential in diagnosis and treatment. We also review the therapeutic strategies targeting circRNAs at both the RNA and protein levels and the delivery systems that support circRNA-directed therapies. After we discuss how circRNA therapeutics may be integrated into precision medicine, we further highlight the current clinical progress and key challenges for advancing circRNA-based therapies toward clinical application.
Background: Bladder cancer is the most common urological malignancy. Bladder cancer has limited therapeutic options, especially in advanced stages. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising target for cancer therapy. However, the role of autophagy in modulating ferroptosis remains incompletely understood.
Methods: We investigated the anti-tumor effects of JS-K, a nitric oxide-releasing prodrug, in bladder cancer through integrated cell, animal, and patient data studies. In vitro experiments with T24 and UM-UC-3 cells were used to explore how JS-K influences cancer cell survival and the interplay between autophagy and ferroptosis. In vivo, a BALB/c nude mouse tumor model provided a system to examine tumor response and tissue-level changes. To extend these findings to the clinical setting, we analyzed LC3B expression and its associations with ferroptosis-related genes, patient prognosis, and the tumor immune microenvironment.
Results: JS-K induced mitochondrial damage, lipid peroxidation, reactive oxygen species accumulation, and intracellular iron overload in bladder cancer cells in a concentration-dependent manner. These changes were accompanied by downregulation of GPX4 and SLC7A11 and upregulation of FTH1 and TFR1, indicative of ferroptosis. Inhibition or knockdown of the autophagy marker LC3B reversed these effects, establishing the role of autophagy in mediating ferroptosis. In xenograft models, JS-K suppressed tumor growth, an effect abrogated by LC3B silencing. Integrated transcriptomic and single-cell analyses revealed a strong correlation between LC3B and ferroptosis-related genes, with CISD1 identified as a key prognostic marker.
Conclusions: JS-K induces autophagy-dependent ferroptosis in bladder cancer cells and significantly suppresses tumor progression. Targeting the autophagy-ferroptosis axis offers a novel therapeutic strategy for bladder cancer treatment.
Background: Intervertebral disc degeneration (IVDD) is a major pathological process leading to low back pain, closely associated with the functional decline of nucleus pulposus progenitor cell (NPPC). The role of the cGAS-STING pathway in mediating DNA-sensing-associated inflammation and senescence in IVDD has not been fully elucidated.
Methods: This study integrated genetics, computational biology, cellular experiments, and animal models to systematically investigate whether taurine (TAU) exerts protective effects by modulating this pathway.
Results: Mendelian randomization analysis suggested a causal relationship between higher TAU levels and reduced risk of IVDD. Molecular docking and dynamics simulations demonstrated that TAU stably binds to cGAS and STING. In both degenerated human nucleus pulposus (NP) tissues and an H2O2-induced NPPC senescence model, the cGAS-STING pathway was significantly activated. TAU intervention maintained mitochondrial function, reduced cytosolic mtDNA leakage, and enhanced autophagic degradation of STING, thereby suppressing downstream TBK1-IRF3/NLRP3 inflammatory signaling and subsequently alleviating cellular senescence, inflammatory responses, and apoptosis. TAU treatment effectively delayed intervertebral disc height loss, histopathological progression, and pain sensitivity in a rat IVDD model.
Conclusion: This study is the first to reveal that TAU mitigates IVDD through multi-targeted modulation of the “mitochondria-cGAS-STING” axis, providing a theoretical foundation for its translational application as a disease-modifying agent.
Protein post-translational modifications (PTMs), such as acetylation, lactylation, methylation, phosphorylation, ubiquitination, and glycosylation, play central roles in regulating diverse cellular processes, including signal transduction, metabolic adaptation, chromatin organization, and proteostasis. In cancer, PTM networks are extensively rewired, with profound alterations in enzyme levels, protein modification landscapes, and crosstalk among different modification types. These changes collectively shape key cancer hallmarks, such as sustained proliferative signaling, immune evasion, and therapeutic resistance. Recent advances in proteomic technologies have enabled comprehensive mapping of PTM landscapes and their regulatory mechanisms, facilitating the identification of PTM signatures associated with tumor subtyping, disease progression, and treatment response. This review summarized biomarkers and therapeutic targets associated with dysregulated PTM regulatory pathways in cancer.
Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract and is mainly driven by activating KIT or PDGFRA mutations. Although tyrosine kinase inhibitors (TKIs) improve outcomes, primary and acquired resistance remain major challenges, especially in high-risk and wild-type GIST. Protein O-linked N-acetylgalactosamine (O-GalNAc) glycosylation regulates protein stability and signaling, but its role in GIST remains unclear.
Methods: Bulk RNA-seq, proteomic, and single-cell RNA-seq data were integrated to identify O-glycosylation-related programs and key glycosyltransferases in GIST. Functional assays in GIST-T1 and GIST-882 cells, together with xenograft models, were performed to assess the effects of GalNAc-transferase 7 (GALNT7). GALNT7-KIT interaction, KIT O-GalNAcylation, and protein stability were examined by co-immunoprecipitation, VVA lectin blotting, confocal microscopy, and cycloheximide chase assays. Benzyl-α-GalNAc was evaluated as an O-glycosylation-targeting strategy in vitro and in vivo.
Results: O-glycosylation signatures were enriched in high-risk GIST and correlated with pathological risk. High O-glycosylation scores co-segregated with elevated copy-number variation in a fibroblast-like malignant cell population. GALNT7 was identified as a hub gene, upregulated in GIST, and associated with poor progression-free survival. GALNT7 promoted GIST cell growth, migration, and xenograft formation. Mechanistically, GALNT7 interacted with KIT, catalyzed its Tn-antigen O-GalNAcylation, increased KIT protein stability, and sustained PI3K/AKT and MAPK/ERK1/2 signaling. Benzyl-α-GalNAc reduced KIT O-GalNAcylation and stability, attenuated GALNT7-driven phenotypes, and inhibited xenograft growth.
Conclusions: GALNT7-mediated O-GalNAc glycosylation stabilizes KIT and drives GIST progression. GALNT7 may serve as a prognostic biomarker and therapeutic target in GIST.