Organoid models reveal mechanistic connections and sirolimus efficacy in liver-vascular steatosis and foam cell formation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are the leading chronic liver diseases globally and are closely linked to systemic metabolic disturbances and cardiovascular risk. Using hepatobiliary and vascular organoid models, this study probes the mechanistic crosstalk between hepatic steatosis and vascular pathology central to MASLD/MASH and early atherosclerosis. Induction of steatosis and inflammation in hepatobiliary organoids triggered the emergence of lipid laden, CD68, CD36 and CD80 positive foam cell-like cells within the liver organoids. Similarly, vascular organoids developed foam cells when exposed to effluent from steatotic liver organoids, highlighting a liver-vascular axis in metabolic disease progression. Treatment with sirolimus, an mTOR inhibitor with known anti-atherogenic properties, significantly reduced both hepatic steatosis and foam cell-like cell numbers in liver and vascular organoids and significantly reduced phospho-mTOR levels in steatotic hepatobiliary organoids which further adds strength to the possibility that foam cells form in steatotic livers. This dual effect supports the therapeutic potential of sirolimus in targeting interconnected liver and vascular lipid pathologies. Additionally, both organoid types exhibited cytoskeletal disruption linked to palmitic acid, a dietary fatty acid implicated in metabolic disease. Differential nuclear morphology responses in liver versus vascular organoids further underscore distinct stress adaptations in these tissues. Our findings reveal that foam cell formation is a convergent feature of MASLD/MASH and vascular injury, underscoring a shared mechanistic axis. This organoid platform offers a novel in vitro system to dissect liver-vascular interactions and evaluate pharmacologic interventions such as sirolimus, suggesting promising avenues for therapeutic strategies addressing cardiometabolic disease.