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Few therapeutic options are available for HCC patients due to intrinsic drug resistance or the low efficacy of conventional chemotherapeutic drugs, including genotoxic agents. We previously demonstrated that adipose triglyceride lipase (ATGL) is downregulated in HCC and shows anti-neoplastic activity by affecting sensitivity to different therapeutic approaches. On the basis of this evidence, we assessed the contribution of ATGL activity to the modulation of the DNA damage response induced by genotoxic drugs. We modulated ATGL expression via overexpression and silencing in the presence of etoposide and doxorubicin, which are genotoxic drugs. The catalytic activity of ATGL was abrogated by a selective inhibitor (ATGListatin) or the overexpression of the ATGL catalytic mutant. To assess the DNA damage response, we evaluated the phosphorylation of H2AX histones and the post-translational modifications of p53. The sensitivity to genotoxic drugs was assessed by analyzing cell viability and molecular markers associated with cell cycle arrest and cell death. Our results demonstrate that ATGL enhances DNA damage in HCC cells in response to genotoxic stimuli. The underlying molecular mechanism involves ATGL-mediated activation of PPAR\u03b1\/p300 signaling. As a result, we observed an imbalance in p53 acetylation\/phosphorylation status that restrains cell cycle arrest and DNA damage repair while promoting apoptotic cell death. In line with the in vitro findings, bioinformatic analyses revealed a strong correlation between ATGL and the PPAR\u03b1\/p300 axis and further demonstrated an enrichment of gene sets associated with cell cycle regulation and DNA damage response in ATGL-high HCC. In conclusion, ATGL levels can be used as a predictive marker of HCC sensitivity to genotoxic insults. The activation of this lipase, or downstream molecular signaling, may thus be exploited to increase the efficacy of chemotherapeutic treatments in HCC.<\/jats:p>","DOI":"10.1038\/s41420-026-03048-4","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T08:33:24Z","timestamp":1773995604000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ATGL sensitizes hepatocellular carcinoma cells to genotoxic drugs by modulating p53 acetylation\/phosphorylation status"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5857-8049","authenticated-orcid":false,"given":"Serena","family":"Castelli","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7696-6192","authenticated-orcid":false,"given":"Angela","family":"De Cristofaro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1884-7491","authenticated-orcid":false,"given":"Enrico","family":"Desideri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Salvi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Ciccarone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7863-9029","authenticated-orcid":false,"given":"Maria Rosa","family":"Ciriolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"3048_CR1","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1126\/science.abi6378","volume":"376","author":"BD Larsen","year":"2022","unstructured":"Larsen BD, Benada J, Yung PYK, Bell RAV, Pappas G, Urban V, et al. 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