Kindlin-1 promotes mitophagy by inhibiting PINK1 degradation to enhance hepatocellular carcinoma progression and modulates sensitivity to donafenib.

Mitophagy, essential for mitochondrial homeostasis, may affect hepatocellular carcinoma (HCC) progression and drug sensitivity, though its precise role remains unclear. Kindlin-1 is an adhesion protein which can regulate the function of integrins, resulting in an aggressive phenotype in certain solid malignant tumors.This study explored the clinical significance and cellular functions of Kindlin-1 in HCC. The role of Kindlin-1 in HCC progression was assessed, along with its effects on mitophagy and sensitivity to donafenib. Its impact on HCC cell proliferation and metastasis was analyzed using CCK8, colony formation, EdU incorporation, flow cytometry, Immunohistochemistry, Transwell assays, wound healing assays, and subcutaneous tumorigenesis in nude mice. The interactions of Kindlin-1 with other proteins and its main functions and pathways were investigated through RNA sequencing, enrichment analysis, immunohistochemical co-localization, Co-IP and mass spectrometry. Additionally, the effects of Kindlin-1 on PINK1 stability and mitophagy were evaluated, and the impact of Kindlin-1 inhibition on donafenib sensitivity was tested in vitro and in vivo. Kindlin-1 was found to be highly expressed in HCC tissues and correlated with a poor prognosis. Kindlin-1 promotes mitophagy by stabilizing full-length PINK1 and prevents ubiquitin induced degradation of PINK1 by interacting with it, thus promoting HCC cell proliferation. Inhibition of Kindlin-1 expression or mitophagy synergistically enhances the anti-tumor effects of donafenib in vitro and in xenograft mouse models. Our study demonstrates that Kindlin-1 significantly influences HCC progression by regulating mitophagy through the PINK1/Parkin pathway. Inhibiting Kindlin-1 may represent a promising therapeutic strategy to enhance the efficacy of donafenib, thereby providing novel insights into improving treatment outcomes for HCC patients.