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This review elucidates the pivotal role of the hepatic nuclear factor-1 family (HNF-1\u03b1 and HNF-1\u03b2) in renal lipid homeostasis, integrating clinical and experimental evidence. Functionally, HNF-1 isoforms regulate lipid synthesis, oxidation, and transport via conserved POU domains and transcriptional networks. HNF-1\u03b1 enhances high-density lipoprotein (HDL)-mediated cholesterol efflux through ApoM, while concurrently regulating PCSK9 to promote LDL receptor (LDLR) endocytosis and degradation, thereby inhibiting cholesterol uptake; whereas, HNF-1\u03b2 promotes cholesterol synthesis via activation of HMGCR\/SREBF2 and modulates the PCSK9-LDLR axis. Additionally, HNF-1\u03b2 coordinates triglyceride metabolism through farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor gamma (PPAR\u03b3) signaling pathways, and regulates mitochondrial fatty acid \u03b2-oxidation (FAO) via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). Clinically, HNF-1\u03b1 (MODY3) and HNF-1\u03b2 (MODY5) mutations are closely associated with dyslipidemia, proteinuria, and CKD progression, with lipotoxicity serving as a key pathogenic driver. Therapeutic strategies targeting HNF-1 include pharmacological agents (e.g., metformin, GLP-1 agonists) and natural compounds (berberine, resveratrol) that modulate its transcriptional activity, alongside CRISPR and miRNA-based precision interventions. This review summarizes the important and multifaceted role of HNF-1 in renal metabolic disorders, highlighting its potential as a therapeutic target and offering new strategies for precision nephrology.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>\u2022 The HNF-1 transcription factor regulates renal lipid metabolism by coordinating lipid synthesis, transport, and fatty acid oxidation.<\/jats:p>\n                  <jats:p>\u2022 The HNF-1\u03b1\/\u03b2 maintains renal cholesterol homeostasis by regulating the HMGCR, PCSK9-LDLR, and ApoM pathways.<\/jats:p>\n                  <jats:p>\u2022 HNF-1\u03b2 deficiency impairs the PPARGC1A pathway, leading to dysfunction of fatty acid \u03b2-oxidation in the renal tubules.<\/jats:p>\n                  <jats:p>\u2022 Targeting HNF-1 offers a novel precision therapy strategy for diabetic nephropathy.<\/jats:p>","DOI":"10.1007\/s10565-025-10097-5","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T01:50:52Z","timestamp":1764121852000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte nuclear factor 1 in renal lipid metabolism: molecular mechanisms and therapeutic potentials"],"prefix":"10.1007","volume":"41","author":[{"given":"Wenhui","family":"Zhu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenfan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yayun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolin","family":"Tong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingfeng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linhua","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"10097_CR1","unstructured":"Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990\u20132021: a systematic analysis for the Global Burden of Disease Study 2021. 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