A Novel CAVIN1/GAS5 Axis Suppresses Skin Fibrosis through Mitochondrial Fission-Mediated Attenuation of the TGF-β/Smad Pathway

Abstract

Background Keloids, which are characterized by excessive collagen deposition and fibroblast hyperactivation, present significant therapeutic challenges because of their high recurrence rates and incompletely understood pathogenesis. The transforming growth factor-β (TGF-β) pathway is a central driver, but its upstream regulators in the development of skin fibrosis remain elusive. Methods We integrated results of transcriptomic and proteomic analyses of patient-derived keloid and normal skin tissues. Functional validation was performed by using primary keloid fibroblasts (KFs) with gain- and loss-of-function approaches, RNA immunoprecipitation sequencing (RIP-seq), and actinomycin D chase assays. Two independent bleomycin-induced skin fibrosis mouse models were employed for in vivo validation. Results Multiomics profiling revealed that caveolae-associated protein 1 (CAVIN1) was consistently downregulated in keloids. CAVIN1 overexpression in KFs suppressed fibrotic phenotypes, including migration, invasion, collagen contraction, and ECM protein expression. Mechanistically, CAVIN1 directly bound to and stabilized the mitochondrial long noncoding RNA GAS5. This CAVIN1/GAS5 axis inhibited Drp1/Fis1-mediated mitochondrial fission and subsequent reactive oxygen species (ROS) production, leading to the attenuation of the canonical TGF-β/Smad2/3 signalling pathway. Critically, GAS5 silencing abrogated the antifibrotic effects of CAVIN1. Furthermore, database screening revealed that the histone deacetylase inhibitor vorinostat was a CAVIN1-upregulating compound. Both AAV-mediated CAVIN1 overexpression and vorinostat treatment significantly ameliorated skin fibrosis in the mouse models. Conclusions Our study reports a novel CAVIN1/GAS5 axis that concurrently targets mitochondrial fission and the TGF-β/Smad pathway to suppress skin fibrosis. These findings not only reveal a previously unrecognized mechanistic link in keloid pathogenesis but also identify CAVIN1 as a promising therapeutic target, with vorinostat as a potential repurposable drug for treating fibrotic skin disorders.