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PGAM5 is a serine\/threonine\/histidine phosphatase that plays a role in mitochondrial biogenesis, mitophagy, and multiple cell death pathways. Increased expression of PGAM5 in hepatocellular carcinoma is correlated with reduced patient survival. In this study, we demonstrate that loss of PGAM5 alters the bioenergetic landscape of liver cancer by promoting mitochondrial oxidant injury and suppressing the glycerophospholipid and lysophospholipid pathways, leading to accumulation of the bioactive phospholipid lysophosphatidylcholine. Additionally,\n                  <jats:italic>PGAM5<\/jats:italic>\n                  deletion downregulates fatty acid biosynthesis, resulting in reduced cellular diacylglycerol concentrations through two probable mechanisms: attenuated long chain fatty acid uptake and suppressed\n                  <jats:italic>de novo<\/jats:italic>\n                  synthesis. These findings underscore the broad impact of a single phosphatase on mitochondrial function and provide a rationale for therapeutically targeting PGAM5 to disrupt lipid metabolism in hepatocellular carcinoma.\n                <\/jats:p>","DOI":"10.64898\/2026.05.01.718031","type":"posted-content","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T06:50:15Z","timestamp":1778050215000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>Phosphoglycerate mutase 5<\/i>\n                  regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9612-8097","authenticated-orcid":false,"given":"Praveen Kumar","family":"Guttula","sequence":"first","affiliation":[{"name":"Department of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesan","family":"Muthusamy","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0723-8313","authenticated-orcid":false,"given":"Chin-Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Office of Research and Graduate Education, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla","family":"Devora","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2192-7051","authenticated-orcid":false,"given":"Emi","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Louisiana Animal Disease Diagnostic Laboratory and Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Butsch","sequence":"additional","affiliation":[{"name":"Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasand","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9081-9017","authenticated-orcid":false,"given":"James","family":"Moran","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6243-6780","authenticated-orcid":false,"given":"Manas Ranjan","family":"Gartia","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1082-1155","authenticated-orcid":false,"given":"Andrea N.","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"},{"name":"Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026050821201127000_2026.05.01.718031v1.1","doi-asserted-by":"crossref","first-page":"4173","DOI":"10.3390\/ijms22084173","article-title":"Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD\/NASH to HCC","volume":"22","year":"2021","journal-title":"Int. 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