{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:48:43Z","timestamp":1791953323983,"version":"4.3.4"},"reference-count":52,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:00:00Z","timestamp":1790985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 112-2320-B-002-030-MY2"],"award-info":[{"award-number":["NSTC 112-2320-B-002-030-MY2"]}]},{"award":["NSTC 112-2320-B-002-030-MY2"],"award-info":[{"award-number":["NSTC 112-2320-B-002-030-MY2"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The growing aging population has been accompanied by an increasing prevalence of chronic kidney disease (CKD), highlighting the need to better understand modifiable dietary and metabolic factors that contribute to renal injury. Folate deficiency and excessive fructose intake have been implicated in renal inflammation; however, the underlying cellular mechanisms remain incompletely understood. In this study, we investigated the effects of folate deficiency or fructose exposure on inflammatory responses, lactate metabolism, oxidative stress, and mitochondrial function in human renal tubular epithelial HK-2 cells. Folate deficiency markedly increased the secretion of the pro-inflammatory cytokines interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), accompanied by enhanced NF-\u03baB activation, both in the presence and absence of lipopolysaccharide (LPS) stimulation. Notably, folate-deficient cells exhibited increased lactate dehydrogenase (LDH) activity, intracellular lactate accumulation, and lactate secretion. Exogenous lactate supplementation or modulation of lactate production using the LDH inhibitor oxamate further demonstrated that elevated lactate promoted IL-6 and transforming growth factor-\u03b21 (TGF-\u03b21) production, NF-\u03baB activation, and reactive oxygen species (ROS) generation. Consistent with these findings, folate deficiency significantly reduced the oxygen consumption ratio (OCR), indicating impaired mitochondrial function and a metabolic shift away from oxidative phosphorylation toward increased lactate production. High fructose exposure also enhanced IL-6 and MCP-1 secretion, particularly following LPS stimulation, while both LPS exposure and folate deficiency further increased lactate production. Collectively, these findings identify lactate accumulation as a potential metabolic link between folate deficiency, inflammation, oxidative stress and fibrotic signaling in renal tubular HK-2 cells. This metabolic-inflammatory pathway may contribute to the initiation and progression of CKD and highlights folate status and lactate metabolism as potential targets for preventing diet-associated renal injury.<\/jats:p>","DOI":"10.3390\/ijms27198846","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:31:31Z","timestamp":1791203491000},"page":"8846","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Folate Deficiency Drives Metabolic Dysfunction, Oxidative Stress, and Inflammation in HK-2 Renal Tubular Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Te-I","family":"Chiu","sequence":"first","affiliation":[{"name":"Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiang-Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bi-Fong","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"V\u00e1squez, F., Tiscornia, C., Aicardi, V., and V\u00e1squez, S. 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