# The TWEAK–HOIP–HuR Axis: A Novel Mechanism of AMPK Inactivation and Metabolic Reprogramming in Lupus Nephritis Mesangial Cells Hyperproliferation

## TL;DR

This study identifies a new signaling pathway involving TWEAK, HOIP, and HuR that causes abnormal cell growth in lupus nephritis, offering potential new treatment targets.

## Contribution

The study reveals a novel TWEAK–HOIP–AMPK–HuR signaling axis linking metabolic changes to cell proliferation in lupus nephritis.

## Key findings

- TWEAK signaling causes AMPK inactivation via HOIP-mediated ubiquitination.
- AMPK suppression leads to cytoplasmic HuR accumulation and Cyclin D1 mRNA stabilization.
- HOIP depletion reverses AMPK inactivation and reduces mesangial cell proliferation.

## Abstract

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‐like weak inducer of apoptosis (TWEAK) signaling and Human antigen R (HuR)‐driven 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‐activated protein kinase (AMPK)—a master regulator of cellular energy metabolism—mediated by the E3 ubiquitin ligase HOIL‐1‐interacting 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‐binding 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‐established 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–HOIP–AMPK–HuR 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.