{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T08:23:59Z","timestamp":1787387039601,"version":"build-2736575974"},"reference-count":26,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":233,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82474471"],"award-info":[{"award-number":["82474471"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Renal fibrosis is a central pathological process in chronic kidney disease (CKD). Although Haikun Shenxi Capsule (HKSX) has shown clinical efficacy in CKD, its precise molecular targets and mechanisms remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aims to determine whether HKSX exerts antifibrotic effects in CKD by modulating NKD2 expression via METTL3\u2010mediated m6A pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A CKD mouse model was established by unilateral ureteral obstruction (UUO). Mice were divided into Sham, Model, low\u2010dose HKSX, high\u2010dose HKSX, and positive drug groups. Renal pathology and fibrosis were assessed by H&amp;E, Masson\u2019s trichrome, and Sirius red staining. Renal function was evaluated by measuring serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Inflammatory cytokines, oxidative stress markers, apoptosis\u2010related proteins, fibrotic markers, NKD2, and METTL3 were detected by ELISA, qPCR, and Western blotting. Global m6A levels and NKD2 mRNA\u2010specific m6A enrichment were measured by colorimetric assay and MeRIP\u2010qPCR, respectively. Renal\u2010specific METTL3\u2010overexpressing mice were generated via lentivirus to validate target dependency. The role of the m6A reader IGF2BP3 was investigated using RIP\u2010qPCR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HKSX significantly improved renal function and attenuated renal pathological injury, inflammation, oxidative stress, apoptosis, and fibrosis in UUO mice. Mechanistically, HKSX dose\u2010dependently downregulated METTL3 expression, reduced both global renal m6A levels and NKD2 mRNA\u2010specific m6A modification, and consequently inhibiting NKD2 overexpression. The protective effects of HKSX were largely abrogated in METTL3\u2010overexpressing CKD mice. Furthermore, HKSX specifically inhibited the expression of the m6A reader IGF2BP3 and its binding to NKD2 mRNA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrates that HKSX alleviates renal fibrosis by inhibiting METTL3, which reduces m6A modification on NKD2 mRNA, and by downregulating the stability reader IGF2BP3. These effects collectively decrease NKD2 mRNA stability and protein expression. These findings reveal a novel epitranscriptomic mechanism of HKSX and identify the METTL3\/IGF2BP3\/NKD2 axis as a key therapeutic pathway in CKD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/mi\/4365859","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T07:59:02Z","timestamp":1787385542000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Haikun Shenxi Capsule Alleviates Renal Fibrosis in CKD Mice by Targeting the METTL3\/IGF2BP3\u2010Mediated m6A Modification of NKD2"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9677-8279","authenticated-orcid":false,"given":"Mingjia","family":"Gu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3080-7659","authenticated-orcid":false,"given":"Le","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7242-3931","authenticated-orcid":false,"given":"Anjing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6841-1311","authenticated-orcid":false,"given":"Neng","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3929-5810","authenticated-orcid":false,"given":"Ying","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3803-4787","authenticated-orcid":false,"given":"Fang","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7171-8237","authenticated-orcid":false,"given":"Xuejing","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0828-1507","authenticated-orcid":false,"given":"Kejian","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3967-8815","authenticated-orcid":false,"given":"Xiaolan","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.221427"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2019.09.003"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmjgh-2021-007525"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-024-00854-w"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2013.04.011"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2016.54"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2941-1"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1159\/000518254"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013101143"},{"key":"e_1_2_10_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3785"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202412123"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.pmbts.2019.03.011"},{"key":"e_1_2_10_13_2","first-page":"2156","article-title":"[Effects of Haikun Shenxi on Expression of Platelet-Derived Growth Factor-B and mRNA in Renal Tissue of Rats With Adriamycin Nephropathy]","volume":"32","author":"Zhao Z. 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