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As such, its regulation is crucial for cell and organismal physiology. Indeed, PPAR\u03b3\u2019s activity is regulated by multiple mechanisms, including post-transcriptional modifications, which, when dys-coordinated, may contribute to the pathogenesis of various states, including obesity, insulin resistance, and fatty liver disease. Here, we demonstrate that SETD6 binds to and methylates PPAR\u03b3 at lysine 170 (K170) both in vitro and in liver-derived cells. This methylation event, in turn, is required for PPAR\u03b3-mediated activation of\n                    <jats:italic>SETD6<\/jats:italic>\n                    transcription via promoter binding, forming a positive feedback regulatory loop. RNA-sequencing revealed that both SETD6 and PPAR\u03b3 methylation at K170 are required for full induction of lipid metabolism genes\u2019 expression, manifesting functionally in lipid droplet biogenesis in liver-derived cells. Together, our findings uncover a novel role for lysine methylation of PPAR\u03b3 in the regulation of lipid synthesis and lipid droplet biogenesis, thereby identifying putative new therapeutic targets for lipid overproduction diseases, including metabolic dysfunction-associated fatty liver disease and obesity.\n                  <\/jats:p>","DOI":"10.7554\/elife.111542","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T14:39:10Z","timestamp":1778769550000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.111542","source":"Crossref","is-referenced-by-count":0,"title":["SETD6-mediated methylation of PPAR\u03b3 establishes a transcriptional feedback circuit promoting lipid accumulation in liver-derived cells"],"prefix":"10.7554","volume":"15","author":[{"given":"Noa","family":"Nashnaz","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05tkyf982","id-type":"ROR","asserted-by":"publisher"}],"name":"The Shraga Segal Department of 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