HRS sustains mitochondrial homeostasis by anchoring destabilized proteins during tumorigenesis

The role of the endosomal sorting complex required for transport (ESCRT) in tumorigenesis remains controversial and context-dependent, with its subunits often exhibiting opposing functions across cancer types. The ESCRT-0 component HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) has been linked to both tumor-suppressive and pro-oncogenic processes, yet its impact on tumor initiation and metabolic adaptation is poorly understood. Here, using a transgenic melanoma model, we demonstrate that melanocyte-specific deletion of HRS delays tumor onset, suppresses tumor growth, and prolongs survival. HRS-deficient tumor cells exhibit a shift toward glycolytic metabolism and impaired proliferation under energy stress. We further show that HRS loss leads to mitochondrial dysfunction, marked by disrupted morphology, reduced tricarboxylic acid (TCA) cycle metabolites, and decreased respiratory enzyme levels. Mechanistically, HRS deficiency disrupts the FYVE- and UIM domain-dependent endosomal clearance of ubiquitinated misfolded proteins, leading to their translocation into mitochondria. This aberrant accumulation triggers a mitochondrial unfolded protein response (mtUPR) and compromises mitochondrial function. Clearance of misfolded proteins from mitochondria rescues these defects. Our study reveals a non-canonical role for HRS in maintaining mitochondrial proteostasis and supporting tumor metabolic plasticity, highlighting HRS as a potential target for disrupting tumor metabolic adaptation.