{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:46:21Z","timestamp":1782279981572,"version":"3.54.5"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"\n Background<\/jats:title>\n \n Colon adenocarcinoma (COAD) shows marked clinical heterogeneity, and robust biomarkers with mechanistic relevance are still needed for prognostic stratification.\n RBMS3<\/jats:italic>\n has been implicated in tumor biology, but its pan-cancer significance, prognostic value in COAD, and regulatory mechanisms remain insufficiently defined.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We performed integrated analyses of The Cancer Genome Atlas pan-cancer and COAD cohorts, followed by external validation in GEO datasets. Prognostic associations were evaluated by Cox and Kaplan-Meier analyses, and clinicopathological relevance was assessed in TCGA-COAD. A prognostic nomogram combining\n RBMS3<\/jats:italic>\n and clinical variables was constructed. Single-cell RNA-seq analysis was used to characterize\n RBMS3<\/jats:italic>\n -associated functional programs.\n In vitro<\/jats:italic>\n experiments in HCT116 cell and THP-1-derived M2 macrophage co-culture systems were conducted to validate ferroptosis-related effects and upstream\n STAT3<\/jats:italic>\n -dependent regulation.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n RBMS3<\/jats:italic>\n was significantly dysregulated across multiple tumor types and showed prognostic relevance in pan-cancer analysis, with a prominent adverse survival association in COAD. GEO cohorts confirmed decreased\n RBMS3<\/jats:italic>\n expression in tumor samples relative to normal controls, and low\n RBMS3<\/jats:italic>\n expression was associated with unfavorable prognosis, supporting its tumor-suppressive prognostic role. In TCGA-COAD,\n RBMS3<\/jats:italic>\n expression correlated with T stage and pathological stage, and integration of\n RBMS3<\/jats:italic>\n with staging factors improved prognostic stratification in a nomogram model. Single-cell analysis showed enrichment of ferroptosis-related pathways in\n RBMS3<\/jats:italic>\n -positive tumor cells. Functionally,\n RBMS3<\/jats:italic>\n overexpression in HCT116 cells reduced viability, decreased GPX4, increased\n ACSL4<\/jats:italic>\n , and elevated intracellular Fe ion levels, indicating molecular features consistent with enhanced ferroptotic sensitivity. Mechanistically, M2 macrophages suppressed\n RBMS3<\/jats:italic>\n expression in tumor cells with concomitant\n STAT3<\/jats:italic>\n activation, while pharmacological\n STAT3<\/jats:italic>\n inhibition partially restored\n RBMS3<\/jats:italic>\n expression.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n RBMS3<\/jats:italic>\n is a clinically relevant prognostic biomarker in COAD and is linked to ferroptosis-associated tumor-cell programs. The M2 macrophage-\n STAT3<\/jats:italic>\n -\n RBMS3<\/jats:italic>\n axis provides a mechanistic connection between the immune microenvironment and tumor intrinsic regulation, highlighting\n RBMS3<\/jats:italic>\n as a potential target for prognostic modeling and translational intervention in COAD.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fmolb.2026.1872659","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:46:10Z","timestamp":1782276370000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["RBMS3 promotes ferroptosis in colorectal cancer and is suppressed by M2 tumor-associated macrophages via STAT3 activation"],"prefix":"10.3389","volume":"13","author":[{"given":"Haiying","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Affiliated Beijing Rehabilitation Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Beijing Rehabilitation Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Beijing Rehabilitation Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Beijing Rehabilitation Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Beijing Rehabilitation Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfang","family":"Shuai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Beijing Rehabilitation Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Beijing Rehabilitation Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanyue","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Beijing Rehabilitation Hospital of Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6430","DOI":"10.1038\/s41388-021-02030-x","article-title":"RNA binding protein RBMS3 is a common EMT effector that modulates triple-negative breast cancer progression via stabilizing PRRX1 mRNA","volume":"40","author":"Block","year":"2021","journal-title":"Oncogene"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2026.01.008","article-title":"Decoding GPX4 regulation in ferroptosis: mechanisms and therapeutic implications","author":"Chen","year":"2026","journal-title":"Trends Mol. 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