Reference - Detail
| RRC ID | 87324 |
|---|---|
| Author | Chu T, Liu Z, Liu H, Mu W, Zhi Y, Sheng N, Zhang J, Peng X, Lv S, Duan K, Lou F, Liu H, Wang C, Zhou J, Liu X, Yang H, Liu Y, Xu J, Fan Z, Wei F. |
| Title | Arachidonic acid induces pyroptosis via a non-autophagic function of mitophagy and enhances immunotherapy in a PDAC model. |
| Journal | Nat Commun |
| Abstract |
Pancreatic ductal adenocarcinoma (PDAC) presents a therapeutic hurdle owing to its immunotherapy resistance and limited treatment options. Pyroptosis, a lytic inflammatory cell death pathway, holds promise for reversing immunosuppression in "cold" tumors, yet tumor-specific induction strategies remain unclear. Here, we employ a contrastive learning graph neural network to identify arachidonic acid (AA), an endogenous ω-6 polyunsaturated fatty acid, as a pan-cancer pyroptosis inducer operating through irreversible mitochondrial permeability transition inducing Caspase 3/GSDME activation. Crucially, a repurposed mitophagy machinery for non-autophagic functional scaffolding of Caspase 3/GSDME on autophagosomal membranes enables rapid pyroptotic execution. Pharmacological accumulation of autophagosomes amplifies AA-induced pyroptosis in PDAC organoids and patient-derived xenografts. Furthermore, AA-triggered pyroptosis, remodels immunosuppressive tumor microenvironments, boosting cytotoxic T cell infiltration and synergizing with anti-PD-1 therapy in immunocompetent models. Thus, our findings position AA as a candidate dual-function agent for pyroptosis-immune synergy, while autophagosome manipulation emerges as a strategy to potentiating strategy. |
| Volume | 17(1) |
| Pages | 1545 |
| Published | 2026-1-10 |
| DOI | 10.1038/s41467-025-68267-2 |
| PII | 10.1038/s41467-025-68267-2 |
| PMID | 41519804 |
| PMC | PMC12894901 |
| MeSH | Animals Arachidonic Acid* / pharmacology Autophagosomes / drug effects Autophagosomes / metabolism Carcinoma, Pancreatic Ductal* / drug therapy Carcinoma, Pancreatic Ductal* / immunology Carcinoma, Pancreatic Ductal* / pathology Carcinoma, Pancreatic Ductal* / therapy Caspase 3 / metabolism Cell Line, Tumor Disease Models, Animal Humans Immunotherapy* / methods Mice Mitophagy* / drug effects Pancreatic Neoplasms* / drug therapy Pancreatic Neoplasms* / immunology Pancreatic Neoplasms* / pathology Pancreatic Neoplasms* / therapy Pyroptosis* / drug effects Tumor Microenvironment / drug effects Tumor Microenvironment / immunology Xenograft Model Antitumor Assays |
| IF | 12.121 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Bluesky |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | PANC-1(RCB2095) RBE(RCB1292) Hep G2 A549 T24 A172(RCB2530) |