The mitochondrial protein Timm13 promotes liver fibrosis by activating TGFβ signaling through Hsp90aa1.

Liver fibrosis is a pathological consequence of chronic liver injury that is reversible but can potentially progress to serious complications. Currently, due to the incomplete elucidation of its key molecular driving mechanisms, effective targeted therapeutic approaches remain lacking in clinical practice. The mitochondrial inner membrane transporter Timm13 has been implicated in cellular stress and disease, yet its role in liver fibrosis remains unclear. This study found that Timm13 is significantly upregulated in human fibrotic liver tissue. Functional studies demonstrated that Timm13 overexpression promotes the activation, proliferation, migration, and extracellular matrix production of hepatic stellate cells (HSCs), whereas Timm13 knockdown inhibits these processes. In a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis, Timm13 overexpression exacerbated collagen deposition and histopathological damage, whereas its knockdown exerted a protective effect. Mechanistically, Co-immunoprecipitation and proteomic analyses identified heat shock protein 90α family member 1 (Hsp90aa1) as a direct binding partner of Timm13. We further demonstrate that this interaction is critical for activating the TGFβ signaling pathway, as Hsp90aa1 silencing reverses the Timm13-driven upregulation of fibrotic markers and TGFβ1 protein levels. This indicates that Timm13 promotes fibrogenic activity by regulating TGFβ1 expression through Hsp90aa1. Furthermore, studies indicate that Timm13 significantly induces mitochondrial dysfunction in hepatic stellate cells, manifested by reduced mitochondrial membrane potential, elevated reactive oxygen species levels, and impaired ATP synthesis. Our results defined a previously unrecognized Timm13/Hsp90aa1/TGFβ signaling axis, revealing how Timm13, through its interaction with Hsp90aa1, concurrently regulates TGFβ1 expression and integrates mitochondrial stress signals to drive the fibrogenic activity of hepatic stellate cells. This study establishes Timm13 as a potential diagnostic biomarker and therapeutic target for liver fibrosis.