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PTMs involve the covalent attachment of distinct chemical groups, such as succinyl, crotonyl, and lactyl, at specific protein sites, which alter protein structure, function, stability, and activity, ultimately influencing biological processes. Recently, metabolically derived short\u2010chain acylation modifications (with acyl groups containing fewer than six carbon atoms) have been progressively identified, such as butyrylation, succinylation, crotonylation, and lactylation, differing from traditional acetylation in structure, physicochemical properties, function, and regulation. Aberrant short\u2010chain acyl\u2010PTMs are often associated with tumorigenesis. Research highlights that PTMs like succinylation and lactylation are essential in regulating tumor metabolism, drug resistance, and immune responses. This review elucidates the regulatory mechanisms of eight short\u2010chain acyl\u2010PTMs\u2014butyrylation, succinylation, crotonylation, malonylation, glutarylation, 2\u2010hydroxyisobutyrylation, \u03b2\u2010hydroxybutyrylation, and lactylation\u2014that are involved in tumor initiation and progression. Their roles in controlling tumor genomic stability, gene transcription, protein stability, enzyme activity, and nuclear localization are summarized, demonstrating their impact on related biological processes such as tumor metabolism, multi\u2010drug resistance, and immune evasion. Additionally, the review provides an overview of current drug research targeting enzymes that regulate PTMs, offering critical insights to advance therapeutic strategies for cancer treatment.<\/jats:p>","DOI":"10.1002\/cac2.70048","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T08:25:22Z","timestamp":1753345522000},"page":"1247-1284","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Short\u2010chain acyl post\u2010translational modifications in cancers: Mechanisms, roles, and therapeutic implications"],"prefix":"10.34133","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5402-2275","authenticated-orcid":false,"given":"Ting","family":"Wu","sequence":"first","affiliation":[{"name":"China Medical University","place":["Shenyang, P. R. China"]},{"name":"Ministry of Education","place":["Shenyang, P. R. China"]},{"name":"China Medical University","place":["Shenyang, P. 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