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However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that hypoxia-inducible factor 2\u03b1 (HIF-2\u03b1) mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2\u03b1 stimulated mammalian target of rapamycin (mTOR)\u2013 and extracellular signal\u2013regulated kinase-dependent inhibitory transcription factor EB (TFEB) phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago\/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2\u03b1\u2013dependent TFEB regulation only occurred in KCs but not RHMs. Instead, in RHMs, HIF-2\u03b1 promoted mitochondrial reactive oxygen species production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Consequently, myeloid lineage\u2013specific or KC-specific HIF-2\u03b1 depletion or the inhibition of mTOR-dependent TFEB inhibition using antisense oligonucleotide treatment protected against the development of NASH in mice. Moreover, treatment with an HIF-2\u03b1\u2013specific inhibitor reduced inflammatory and fibrogenic gene expression in human liver spheroids cultured under a NASH-like condition. Together, our results suggest that macrophage subtype\u2013specific effects of HIF-2\u03b1 collectively contribute to the proinflammatory activation of liver macrophages, leading to the development of NASH.<\/jats:p>","DOI":"10.1126\/scitranslmed.adi0284","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T17:59:08Z","timestamp":1726077548000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":51,"title":["HIF-2\u03b1 drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9903-6326","authenticated-orcid":true,"given":"Ishtiaq","family":"Jeelani","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, 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