{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T16:52:01Z","timestamp":1786553521109,"version":"build-2736575974"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      METTL3-mediated m\n                      <jats:sup>6<\/jats:sup>\n                      A RNA methylation has been implicated in renal fibrosis, a central pathological feature of chronic kidney disease (CKD). NLRC5, the largest NLR family member, is a direct m\n                      <jats:sup>6<\/jats:sup>\n                      A target of METTL3, but its role in METTL3-driven renal fibrosis remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      An\n                      <jats:italic>in vitro<\/jats:italic>\n                      renal fibrosis model was established using TGF-\u03b21\u2013stimulated human proximal tubular (HK-2) cells. METTL3-mediated m\n                      <jats:sup>6<\/jats:sup>\n                      A modification and stabilization of NLRC5 mRNA were assessed by m\n                      <jats:sup>6<\/jats:sup>\n                      A quantification, RNA stability, MeRIP, and RIP assays. Functional impacts on the Keap1\/Nrf2\/ARE pathway and fibrotic responses were examined using METTL3 inhibition (STM2457, 10 \u03bcM), NLRC5 knockdown or overexpression, Keap1 overexpression, and Nrf2 inhibition (ML385, 5 \u03bcM). Fibrotic markers, inflammatory cytokines (IL-1\u03b2, TNF-\u03b1; ELISA), and oxidative stress (ROS\/DCF-DA, SOD, MDA) were measured. NLRC5-overexpression effects on the Keap1\/Nrf2\/ARE pathway were additionally evaluated.\n                      <jats:italic>In vivo<\/jats:italic>\n                      validation employed a unilateral ureteral obstruction (UUO) mouse model, with kidney injury and fibrosis assessed via H&amp;amp;E, Masson\u2019s staining, IHC, ELISA, Western blot, and qRT-PCR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TGF-\u03b21 upregulated METTL3, NLRC5, and global m\n                      <jats:sup>6<\/jats:sup>\n                      A levels in HK-2 cells. METTL3 directly bound and stabilized NLRC5 mRNA via m\n                      <jats:sup>6<\/jats:sup>\n                      A modification. METTL3 overexpression exacerbated TGF-\u03b21-induced inflammation, oxidative stress, and fibrosis, which were reversed by STM2457. Conversely, METTL3 or NLRC5 inhibition suppressed fibrosis, coinciding with Keap1 downregulation and Nrf2\/HO-1\/NQO1 upregulation. Keap1 overexpression negated the anti-fibrotic effects of NLRC5 knockdown, while NLRC5 overexpression decreased nuclear Nrf2 and downstream antioxidant targets, confirming NLRC5\u2019s inhibitory role on Keap1\/Nrf2 signaling. Nrf2 inhibition (ML385) or NLRC5 overexpression rescued METTL3 knockdown phenotypes.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , METTL3 knockdown attenuated UUO-induced renal injury and fibrosis, activating the Keap1\/Nrf2\/ARE pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      METTL3 promotes renal fibrosis by stabilizing NLRC5 mRNA via m\n                      <jats:sup>6<\/jats:sup>\n                      A modification, leading to suppression of the protective Keap1\/Nrf2\/ARE pathway. Targeting the METTL3\/NLRC5\/Keap1\/Nrf2\/ARE axis may represent a promising therapeutic strategy for CKD-associated fibrosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1739011","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T11:05:51Z","timestamp":1773227151000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["METTL3-driven m6A modification of NLRC5 promotes renal fibrosis in chronic kidney disease through Keap1\/Nrf2\/ARE signaling pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Mingzhi","family":"Xu","sequence":"first","affiliation":[{"name":"Blood Purification Center of Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruman","family":"Chen","sequence":"additional","affiliation":[{"name":"Blood Purification Center of Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zeng","sequence":"additional","affiliation":[{"name":"Blood Purification Center of Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjiao","family":"Pan","sequence":"additional","affiliation":[{"name":"Blood Purification Center of Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunli","family":"Wang","sequence":"additional","affiliation":[{"name":"Blood Purification Center of Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghui","family":"Qi","sequence":"additional","affiliation":[{"name":"Blood Purification Center of Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"An","sequence":"additional","affiliation":[{"name":"Blood Purification Center of Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafei","family":"Bai","sequence":"additional","affiliation":[{"name":"Blood Purification Center of Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University","place":["Haikou, Hainan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(20)30045-3","article-title":"Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"395","year":"2020","journal-title":". 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