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Abstract Hepatocellular carcinoma (HCC) is the 3rd most deadly malignancy. Activated hepatic stellate cells (aHSC) give rise to cancer-associated fibroblasts in HCC and are considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase-2 (Scd2) in aHSC globally suppresses nuclear CTNNB1 and YAP1 in tumors and tumor microenvironment and prevents liver tumorigenesis in male mice. Tumor suppression is associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). Genetic or pharmacological inhibition of LTB4R2 recapitulates CTNNB1 and YAP1 inactivation and tumor suppression in culture and in vivo. Single cell RNA sequencing identifies a subset of tumor-associated aHSC expressing Cyp1b1 but no other 12-HHTrE biosynthetic genes. aHSC release 12-HHTrE in a manner dependent on SCD and CYP1B1 and their conditioned medium reproduces the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC are detected in proximity of LTB4R2-positive HCC cells and the growth of patient HCC organoids is blunted by LTB4R2 antagonism or knockdown. Collectively, our findings suggest aHSC-initiated 12-HHTrE-LTB4R2-CTNNB1-YAP1 pathway as a potential HCC therapeutic target.

Cell death is now reclassified into several types based on the mechanisms and morphologic phenotype. Understanding of such classifications offers insights into the pathogenesis of liver disease, as well as diagnostic or therapeutic implications. Apoptosis is recognized relatively easily due to its unique morphology, but lytic cell death may occur in the form of accidental necrosis, mitochondria permeability transition-driven necrosis, necroptosis, pyroptosis, ferroptosis, and parthanatos. The cell may be engulfed by neighboring cells due to a loss of integrin signaling or cancer cell competition by entosis, a type of cell death. The classification also includes mechanistically termed cell death such as autophagy-dependent cell death and lysosome-dependent cell death. These different types of cell death may occur uniquely in certain liver diseases but may coexist in the evolution of the disease. They occur in parenchymal and non-parenchymal liver cells, as well as inflammatory cells, causing distinct pathologic consequences. This review briefly covers the recently revised classifications of cell death and discusses their relevance to liver diseases of different etiologies.