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While it is known that PM2.5 can alter the expression profile of microRNAs in the lung, its specific role in damaging pulmonary epithelial cells remains unclear. This study, therefore, employed RT-qPCR, Western blotting, and dual luciferase reporter assays to investigate the regulatory role of microRNAs in PM2.5-induced cellular damage. PM2.5 exposure induces oxidative stress, autophagy, and ferroptosis in rat lung alveolar epithelial cells (RLE-6TN). Further functional rescue experiments confirm that the ferroptosis-specific inhibitor Fer-1 can block PM2.5-induced ferroptosis. Bioinformatics analysis and validation indicate that miR-212-5p plays a crucial role by negatively regulating RASSF1 through targeted inhibition. Overexpression of miR-212-5p activates the PI3K\/AKT signaling pathway, thereby promoting autophagy and ferroptosis. However, when the expression of both miR-212-5p and RASSF1 is suppressed, PM2.5-induced autophagy and ferroptosis are significantly alleviated by inhibiting the PI3K\/AKT\/mTOR signaling pathway. Rescue validation experiments demonstrated that, under PM2.5 exposure combined with RASSF1 overexpression, miR-212-5p exacerbates the aforementioned cellular damage process. This study reveals that miR-212-5p regulates autophagy and ferroptosis by targeting RASSF1. These findings provide a multi-target intervention strategy for PM2.5-related lung diseases.<\/jats:p>","DOI":"10.3390\/cells15090823","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T14:35:53Z","timestamp":1777559753000},"page":"823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Key Molecular Events in PM2.5-Induced Lung Injury: Autophagy and Ferroptosis Mediated by the miR-212-5p\/RASSF1 Axis"],"prefix":"10.3390","volume":"15","author":[{"given":"Cuizhu","family":"Zhao","sequence":"first","affiliation":[{"name":"College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunna","family":"Jia","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Animal Husbandry and Veterinary Research Institute, Jilin Academy of Agricultural Sciences, Changchun 130033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Du","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Liang","sequence":"additional","affiliation":[{"name":"Institute of Animal Science, Ningxia Academy of Agriculture and Forestry, Yinchuan 750002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuzhen","family":"Yu","sequence":"additional","affiliation":[{"name":"Agricultural Equipment Research Institute of Xinjiang Uygur Autonomous Region, Academy of Agricultural Sciences, Urumqi 830091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5701-6685","authenticated-orcid":false,"given":"Yunhang","family":"Gao","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1136\/thorax-2025-223178","article-title":"Ultrafine particles and health: The next frontier in understanding air pollution hazards","volume":"80","author":"Nicolaou","year":"2025","journal-title":"Thorax"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"114362","DOI":"10.1016\/j.fct.2023.114362","article-title":"Oxidative stress is the pivot for PM2.5-induced lung injury","volume":"184","author":"Hou","year":"2024","journal-title":"Food Chem. 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