{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T20:56:48Z","timestamp":1787950608665,"version":"build-2784847793"},"reference-count":43,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82260148 82170743"],"award-info":[{"award-number":["82260148 82170743"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,5,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Diabetic kidney disease (DKD) constitutes a severe microvascular complication of diabetes and ranks among the leading causes of end\u2010stage renal disease (ESRD). Endoplasmic reticulum stress (ERS) significantly contributes to the initiation and progression of DKD, as persistent ERS leads to excessive activation of the unfolded protein response (UPR), triggering cellular apoptosis. Protein carbonylation, a prominent oxidative modification caused by reactive oxygen species (ROS), is recognized as a critical initiator of ERS. Acyl peptide enzyme hydrolase (APEH) demonstrates cytoprotective properties by degrading carbonylated proteins and alleviating their abnormal aggregation. Nonetheless, the precise roles and mechanisms of APEH in DKD remain inadequately elucidated. This study employs 24\u2010week\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice and a renal tubular epithelial cell model stimulated by high glucose and high fat conditions. By combining comprehensive multidatabase bioinformatics analysis, morphological characterization, and molecular biology techniques, we aim to elucidate the functional role and underlying regulatory mechanisms of APEH in DKD. Our findings indicate that DKD is associated with significantly reduced expression of both APEH and hepatocyte nuclear factor 4 alpha (HNF4A), leading to elevated protein carbonylation and subsequent activation of the UPR pathway, ultimately causing increased apoptosis in renal tubular epithelial cells. Further investigation through dual\u2010luciferase reporter assays and ChIP\u2010qPCR analysis confirmed that HNF4A directly regulates APEH expression by binding to its promoter region. Reduced APEH expression impairs the protective effects mediated by HNF4A, resulting in elevated protein carbonylation, enhanced UPR activation, and increased apoptosis, thereby exacerbating renal tubular epithelial cell injury in DKD. Collectively, these findings underscore the critical role of the HNF4A\/APEH axis in regulating protein carbonylation and UPR signaling during DKD progression, highlighting a potential novel therapeutic target for DKD treatment.\n                  <\/jats:p>","DOI":"10.1096\/fj.202500106r","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T10:25:29Z","timestamp":1747823129000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>HNF4A<\/scp>\n                    Regulated\n                    <scp>APEH<\/scp>\n                    Deficiency Promotes\n                    <scp>UPR<\/scp>\n                    Activation in Diabetic Kidney Disease"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8553-4240","authenticated-orcid":false,"given":"Fangfang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, Basic 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