{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:24:37Z","timestamp":1793831077474,"version":"4.6.1"},"reference-count":32,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82404006"],"award-info":[{"award-number":["82404006"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82404006"],"award-info":[{"award-number":["82404006"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Mitoxyperilysis is a recently described form of regulated cell death, but its clinical and immunological relevance in hepatocellular carcinoma (HCC) remains unclear. This study investigated the prognostic significance of mitoxyperilysis-related transcriptional activity and its role in remodeling the tumor immune microenvironment. Methods: A Mitoxyperilysis Score was generated by single-sample gene set enrichment analysis. Prognostic associations were evaluated using Kaplan\u2013Meier analysis, multivariable Cox regression, independent cohort validation, and random-effects meta-analysis. Immune infiltration and cell\u2013cell communication were examined using bulk transcriptomic and single-cell RNA-sequencing data. The functional role of ANXA1 was assessed by ELISA, Western blotting, macrophage co-culture, immunofluorescence, flow cytometry, ANXA1 knockdown, and subcutaneous tumor models. Results: High Mitoxyperilysis Scores were associated with shorter overall survival in TCGA-LIHC (log-rank p = 0.032), although the association was attenuated after adjustment for age, sex, stage, grade, and vascular invasion. The adverse survival association was independently reproduced in the Gao2019 CHCC-HBV cohort (log-rank p = 0.00383). Across TCGA-LIHC, GSE14520, and Gao2019 CHCC-HBV, a random-effects analysis showed an overall hazard ratio of 1.42 per 1-standard-deviation increase in score (95% CI, 1.08\u20131.86; p = 0.011), with substantial between-cohort heterogeneity (I2 = 77.5%). High-score tumors displayed increased immune and stromal infiltration, immune-checkpoint expression, and M2-like macrophage enrichment. ANXA1 expression correlated positively with the Mitoxyperilysis Score in independent cohorts. Mitoxyperilysis induction increased both intracellular and extracellular ANXA1, while ANXA1 overexpression promoted CD163+CD206+ macrophage polarization. ANXA1 knockdown attenuated this response, reduced subcutaneous tumor burden, and decreased intratumoral CD163 staining. Conclusions: Mitoxyperilysis-related transcriptional activity is associated with adverse survival and an M2-enriched immunosuppressive microenvironment in HCC. ANXA1 is an important, although probably not exclusive, mediator of this process and may represent a potential therapeutic target.<\/jats:p>","DOI":"10.3390\/cancers18172786","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T10:58:21Z","timestamp":1787828301000},"page":"2786","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mitoxyperilysis Drives Immunosuppressive Tumor Microenvironment Remodeling and Hepatocellular Carcinoma Progression via ANXA1-Mediated Macrophage M2 Polarization"],"prefix":"10.3390","volume":"18","author":[{"given":"Meng","family":"Qin","sequence":"first","affiliation":[{"name":"General Surgery, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430071, China"},{"name":"Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhi","family":"He","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Wu","sequence":"additional","affiliation":[{"name":"General Surgery, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.jhep.2022.08.021","article-title":"Global burden of primary liver cancer in 2020 and predictions to 2040","volume":"77","author":"Rumgay","year":"2022","journal-title":"J. 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