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However, current clinical treatment options for this process remain limited. In this study, we aimed to investigate the potential benefits of GS\u20104997, a selective inhibitor of ASK1, in tubulointerstitial injury of LN. Female MRL\/lpr mice were used as a classical lupus\u2010prone murine model. Development of nephritis was assessed by monitoring of proteinuria, renal function, and histologic analysis. GS\u20104997 (50\u2009mg\/kg) or vehicle were treated orally. In\u00a0vitro study, human kidney\u20102 (HK\u20102) cells were stimulated with 1\u2009\u03bcg\/mL lipopolysaccharide (LPS) to mimic the response of renal tubular epithelial cells undergoing inflammatory responses during LN. GS\u20104997 could inhibit the activation of the ASK1 in renal tubulointerstitium in MRL\/lpr mice and LPS\u2010induced HK\u20102 cells. GS\u20104997 treatment improved renal function, proteinuria, and attenuated tubular injury, renal interstitial fibrosis, and inflammation both in\u00a0vivo and in\u00a0vitro. Additionally, we found that in MRL\/lpr mice, GS\u20104997 reduced deposition of IgG and C3 in the kidneys, antibody levels in the serum, splenic enlargement, and inflammatory cell infiltration in the spleen. Mechanistically, GS\u20104997 inhibited the activation of downstream signaling molecules, p38 and JNK, in the ASK1 signaling pathway. Pharmacological inhibition of ASK1 may prevent the progression of tubulointerstitial injury via inhibiting the ASK1\/MAPK pathway in LN. Therefore, our findings demonstrate the potential use of GS\u20104997 for LN treatment.<\/jats:p>","DOI":"10.1096\/fj.202401676rr","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T08:08:58Z","timestamp":1734336538000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>GS<\/scp>\n                    \u20104997 halts the progression of tubulointerstitial injury in\u00a0lupus nephritis"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2748-7042","authenticated-orcid":false,"given":"Zheng","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Nephrology, Hunan Clinical Research Center for Chronic Kidney Disease, Hunan Provincial People's Hospital The First Affiliated Hospital of Hunan Normal University  Changsha Hunan People's Republic of 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