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Its intricate pathogenesis and the paucity of efficacious clinical interventions have elevated it to a critical global public health concern. Recently, the intersection of metabolic reprogramming and epigenetic regulation has illuminated that aberrant lactate accumulation associated with dysregulated glycolysis and the ensuing imbalance of histone and non\u2010histone lysine lactylation (Kla) may represent an important molecular link between renal cellular metabolic perturbations and the fibrotic cascade. The dynamic landscape of Kla is regulated by lactate itself, alongside \u201cwriters\u201d (lactoyltransferases), \u201cerasers\u201d (delactylases), and site\u2010specific \u201creaders.\u201d Currently, Kla marks have been extensively mapped across the core histones H2A, H2B, H3, and H4. Notably, histone H3 lysine 18 lactylation (H3K18la), histone H3 lysine 14 lactylation (H3K14la), histone H4 lysine 12 lactylation (H4K12la), and histone H4 lysine 16 lactylation (H4K16la) represent the most rigorously investigated loci within the context of renal fibrosis, where they have been implicated in pathological processes, including tubular epithelial\u2010to\u2010mesenchymal transition, perturbation of the renal inflammatory microenvironment, and mitochondrial impairment. Beyond histone modifications, the biological significance of non\u2010histone Kla is increasingly being recognized. Investigations into specific loci, such as acyl\u2010coenzyme A synthetase family member 2\u2009K182 lactylation (ACSF2\u2010K182la) and PBX homeobox\u00a01\u2009K40 lactylation (PBX1\u2010K40la), are emerging as areas of growing research interest in renal fibrosis. This review systematically synthesizes the metabolic foundations, molecular mechanisms, pathological roles, disease correlations, and targeted therapeutic strategies associated with both histone and non\u2010histone Kla. By integrating cutting\u2010edge discoveries and delineating the challenges confronting contemporary research, we endeavor to provide a comprehensive academic overview. Ultimately, we aim to deepen the mechanistic understanding of Kla in CKD\u2010related renal fibrosis and to inform future investigations into its translational potential for novel diagnostics and therapeutics.<\/jats:p>","DOI":"10.1096\/fj.202602239r","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T07:21:22Z","timestamp":1788765682000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactate\u2010Mediated Lysine Lactylation in Renal Fibrosis: Current Progress and Challenges"],"prefix":"10.1096","volume":"40","author":[{"given":"Weili","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Nephrology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Nephrology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yachen","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Nephrology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinru","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Nephrology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9093-9495","authenticated-orcid":false,"given":"Yong","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Nephrology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(25)01853-7"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01379-7"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1300575"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.7326\/ANNALS-24-01926"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-58563-2"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-025-02519-z"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.70022"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13548"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23169420"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39050-y"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-025-01554-z"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-24-3173"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202302063RR"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202201189RR"},{"key":"e_1_2_13_16_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0121046","article-title":"Tumor Cells Switch to Mitochondrial Oxidative Phosphorylation Under Radiation via mTOR\u2010Mediated Hexokinase II Inhibition \u2010 A Warburg\u2010Reversing Effect","volume":"10","author":"Lu C. 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