{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T15:10:39Z","timestamp":1779117039779,"version":"3.51.4"},"reference-count":78,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T00:00:00Z","timestamp":1778889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Protein lactylation, an emerging post-translational modification (PTM) driven by the metabolite lactate, has surfaced as an important regulatory layer contributing to the crosstalk between metabolic reprogramming and cellular functional plasticity in colorectal cancer (CRC). Within the unique \u201chost\u2013microbiota\u201d symbiotic microenvironment of CRC, the Warburg effect\u2014fueled jointly by oncogene activation and microbial metabolism\u2014provides abundant substrates for lactylation. This modification is dynamically regulated by a complex enzymatic system comprising \u201cWriters\u201d (e.g., p300\/CREB-binding protein [p300\/CBP], alanyl-tRNA synthetase 1\/2 [AARS1\/2]) and \u201cErasers\u201d (e.g., histone deacetylases [HDACs] and Sirtuins). Through intricate crosstalk with other PTMs, such as acetylation and ubiquitination, lactylation exerts critical regulatory effects on both the histone epigenetic landscape and non-histone protein functions. Functionally, lactylation not only drives malignant proliferation, invasion, and metastasis but also systematically remodels the immunosuppressive \u201ccold\u201d tumor microenvironment. Furthermore, it confers broad-spectrum resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy by orchestrating a ferroptosis defense network, enhancing DNA damage repair (DDR), and activating protective autophagy. This review systematically synthesizes the regulatory networks and biological functions of lactylation in CRC, deeply elucidating the core mechanisms underlying therapy resistance. Finally, we discuss the clinical translational potential of lactylation as a novel diagnostic\/prognostic biomarker and therapeutic target, aiming to provide new theoretical foundations and strategic directions for overcoming current bottlenecks in CRC clinical treatment.<\/jats:p>","DOI":"10.3390\/ijms27104480","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T14:40:31Z","timestamp":1779115231000},"page":"4480","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactylation in Colorectal Cancer: Regulatory Networks, Functional Mechanisms, and Clinical Translational Potential"],"prefix":"10.3390","volume":"27","author":[{"given":"Diao","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Oncology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan 430060, China"},{"name":"Renmin Hospital of Wuhan Economic and Technological Department Zone, Wuhan 430090, China"},{"name":"Wuhan University Heavy Ion Medicine Center, Renmin Hospital of Wuhan University, Wuhan Economic and Technological Department Zone, Wuhan 430090, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2841-2612","authenticated-orcid":false,"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan 430060, China"},{"name":"Renmin Hospital of Wuhan Economic and Technological Department Zone, Wuhan 430090, China"},{"name":"Wuhan University Heavy Ion Medicine Center, Renmin Hospital of Wuhan University, Wuhan Economic and Technological Department Zone, Wuhan 430090, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianyu","family":"Lei","sequence":"additional","affiliation":[{"name":"Renmin Hospital of Wuhan Economic and Technological Department Zone, Wuhan 430090, China"},{"name":"Wuhan University Heavy Ion Medicine Center, Renmin Hospital of Wuhan University, Wuhan Economic and Technological Department Zone, Wuhan 430090, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinyong","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuchang District, Wuhan 430060, China"},{"name":"Renmin Hospital of Wuhan Economic and Technological Department Zone, Wuhan 430090, China"},{"name":"Wuhan University Heavy Ion Medicine Center, Renmin Hospital of Wuhan University, Wuhan Economic and Technological Department Zone, Wuhan 430090, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/S0140-6736(24)00360-X","article-title":"Colorectal cancer","volume":"404","author":"Eng","year":"2024","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.suc.2023.11.009","article-title":"Screening for Colorectal Cancer","volume":"104","author":"Jacobsson","year":"2024","journal-title":"Surg. 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