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Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pH<jats:sub><jats:italic>e<\/jats:italic><\/jats:sub>) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pH<jats:sub><jats:italic>e<\/jats:italic><\/jats:sub>, but not at acidic pH<jats:sub><jats:italic>e<\/jats:italic><\/jats:sub>. Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation\u2010induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet\u2010, triacylglycerol\u2010, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator\u2010activated receptor\u2010\u03b1 (<jats:italic>PPARA<\/jats:italic>, PPAR\u03b1) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPAR\u03b1 upregulates genes driving increased mitochondrial and peroxisomal mass and \u03b2\u2010oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin\u2010interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid\u2010adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid\u2010adapted cells exhibit increased sensitivity to PPAR\u03b1 inhibition. We conclude that PPAR\u03b1 is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.<\/jats:p>","DOI":"10.1002\/ijc.34404","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T11:22:00Z","timestamp":1671448920000},"page":"1668-1684","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Chronic acidosis rewires cancer cell metabolism through <scp>PPAR\u03b1<\/scp> signaling"],"prefix":"10.1002","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4139-1218","authenticated-orcid":false,"given":"Michala G.","family":"Rolver","sequence":"first","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lya K. 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