RHOA promotes mechanical overload-induced intervertebral disc degeneration through PI3K/AKT/MYC-mediated TAGLN transcription.

Authors

Helong Zhang, Jie Qiu, Yifei Wang, Tong Chen, Yiming Li, Melanie L Hart, Bernd Rolauffs, Zhenfei Huang, Cheng Ma, Yongxin Ren

Published in

Cellular signalling. Pages 112998. Nov 10, 2026. Epub Nov 10, 2026.

Abstract

Mechanical overload serves as a major initiator of intervertebral disc degeneration (IVDD); however, the molecular mechanisms underlying mechanical overload-induced IVDD remain poorly understood. To identify key mediators of mechanical overload, we performed proteomic analysis of human nucleus pulposus (NP) tissues with different degrees of IVDD and intersected differentially upregulated proteins with a mechanics-related gene set, identifying RHOA as a potential mediator of mechanical stress. RHOA expression was markedly increased in degenerated human NP tissues, a mechanical overload-induced mouse model of IVDD, and human NP cells cultured on stiffer substrates, supporting its association with mechanical stress and IVDD progression. Inhibition of RHOA significantly attenuated extracellular matrix (ECM) remodeling and IVDD progression in vivo and in vitro. Integrated proteomic and transcriptomic analyses revealed a strong association between RHOA expression and apoptosis-related processes, and functional experiments demonstrated that RHOA promoted ECM remodeling, mitochondrial dysfunction, and apoptosis under mechanical stress. Transcriptomic analysis further identified TAGLN as a downstream effector of RHOA-mediated NP cell degeneration. TAGLN overexpression aggravated IVDD and partially reversed the protective effects of RHOA/ROCK inhibition. Mechanistically, RHOA promoted TAGLN transcription through the PI3K/AKT/MYC signaling pathway. Furthermore, mechanical overload induced RHOA expression through activation of the NF-κB signaling pathway. Collectively, these findings identify an NF-κB/RHOA/PI3K/AKT/MYC/TAGLN regulatory axis that links mechanical overload to NP degeneration and IVDD progression, highlighting RHOA as a potential therapeutic target for mechanically induced IVDD.

PMID:
43008962
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.

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