Dysregulated Metabolic-Matrix Axis in MASH/HCC - PROJECT SUMMARY/ABSTRACT The increasing prevalence and severity of metabolic dysfunction associated steatohepatitis (MASH) and its sequelae resulted in a rise in mortality in the aging population. MASH-related hepatocellular carcinoma (HCC) has a poor prognosis in older patients, and the effects of aging-mediated pathways on MASH-driven HCC are not well understood. The Src homology 2 domain containing collagen-related (SHC) adaptor proteins increase during aging in the liver, and inhibiting Shc in MASLD/MASH either genetically or pharmacologically increased beta oxidation and improved inflammation and fibrosis. Based on this, we now propose that age-related maladaptive responses via Shc create a niche that predispose to HCC by mitochondrial dysfunction, decrease in FAO, lipid peroxidation, modulating matrix mechanics to promote cell invasion. To address this hypothesis in Aim 1 we will study dietary as well as Shc isoform-specific knockdowns and inducible transgenic models for MASH/HCC in young vs. old mice. We will evaluate mitochondrial OXPHOS, β-oxidation, as well as the effects of beta hydroxybutyrate production, including HDAC1/2, and p53 acetylation. In Aim 2, we will study matrix mechanics and architecture that are modulated via Shc mediated advanced lipoxygenation products. Force maps will be multiplexed with CODEX to evaluate cell interactome and mechanical characteristics, in situ in MASH/HCC. Detailed analyses of the matrix by LC-MS, SHG microscopy, and modeling using 3D hydrogel systems will be performed. In Aim 3, will investigate how p46Shc and p52Shc inhibition with small-molecule Shc blockers improves MASH and MASH-to-HCC transition, evaluating biochemical, physiological, metabolic as well as matrix endpoints in aged mice, and by in vitro experiments. These studies will elucidate age-specific metabolic-matrix pathways that favor hepatocarcinogenesis and set the stage to develop effective treatment options for the elderly.
