{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T16:27:02Z","timestamp":1784132822349,"version":"3.55.0"},"reference-count":60,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"vor","delay-in-days":60,"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"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>Cellular proliferation is intrinsically coupled to metabolic reprogramming, a conserved biological association that modulates the progression of diverse proliferative pathologies. In the present study, we unveil a novel mechanistic link between tumor necrosis factor\u2010like weak inducer of apoptosis (TWEAK) signaling and Human antigen R (HuR)\u2010driven metabolic alterations in lupus nephritis (LN), a progressive renal disorder characterized by mesangial cells (MCs) hyperproliferation and glomerular dysfunction. We demonstrate that TWEAK stimulation elicits linear ubiquitination of AMP\u2010activated protein kinase (AMPK)\u2014a master regulator of cellular energy metabolism\u2014mediated by the E3 ubiquitin ligase HOIL\u20101\u2010interacting protein (HOIP). This posttranslational modification directly results in the functional inactivation of AMPK. Notably, suppressed AMPK activity drives the nuclear export of HuR, a ubiquitously expressed RNA\u2010binding protein, leading to its subsequent accumulation in the cytoplasmic compartment. In the cytosol, HuR selectively binds to and stabilizes the mRNAs of key cell cycle regulators, with Cyclin D1 being a primary target. This stabilization of Cyclin D1 mRNA ultimately promotes aberrant MCs proliferation, a pathological hallmark of LN. To validate the functional relevance of the pathogenesis, we performed HOIP knockdown experiments in MCs. Consistent with our mechanistic model, HOIP depletion significantly restored AMPK phosphorylation (a well\u2010established surrogate marker of AMPK activation), suppressed HuR cytoplasmic shuttling, reduced Cyclin D1 expression at both the transcriptional and translational levels, and ultimately inhibited aberrant MCs proliferation in vitro. Collectively, our results establish the TWEAK\u2013HOIP\u2013AMPK\u2013HuR axis as a critical signaling axis that couples metabolic dysfunction to dysregulated cell cycle progression in LN. This work not only provides critical new mechanistic insights into the pathogenesis of mesangial hyperproliferation in LN but also highlights potential therapeutic targets, including HOIP and cytoplasmic HuR, for the development of targeted treatments for LN and other renal diseases characterized by abnormal MCs proliferation.<\/jats:p>","DOI":"10.1155\/mi\/4149395","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T12:04:43Z","timestamp":1772971483000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The TWEAK\u2013HOIP\u2013HuR Axis: A Novel Mechanism of AMPK Inactivation and Metabolic Reprogramming in Lupus Nephritis Mesangial Cells 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