Biochimica et biophysica acta. Molecular and cell biology of lipids · 2026
Caveolin-2 knockout suppresses the formation and progression of oral leukoplakia via lipid metabolism disruption.
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Chen Xiao-Jie, Bai Yu-Ting, Jiang Ming-Jing, Dong Bing-Jie, Zhou Gang
Аннотация
BACKGROUND: Caveolin-2 (CAV2) is a lipid droplet (LD)-associated protein. Its role in oral leukoplakia (OLK), an oral potentially malignant disorder, and the underlying lipid metabolism mechanisms remain unclear.
METHODS: CAV2 conditional knockout (cKO; CAV2flox/flox; K14-Cre) and control (Flox) C57BL/6 mice were used to establish OLK models via 4-nitroquinoline-N-oxide (4NQO). A subset received a high-fat diet (HFD). Oil red O staining, RNA sequencing, multiplex immunofluorescence (Ki-67, E-cadherin, Perilipin-1, FABP5), ELISA (acetyl-CoA), serum biochemistry (ALT, TG), and targeted GC-MS/MS fatty acid profiling were performed.
RESULTS: CAV2 knockout significantly suppressed OLK progression, evidenced by reduced lesion diameter/number and attenuated pathological severity. HFD failed to rescue OLK progression. RNA-seq confirmed dysregulation of lipid transport, lipolysis, and fatty acid metabolism/biosynthesis. Targeted metabolomics revealed markedly attenuated carcinogen-induced fatty acid accumulation in cKO mice, with C18:2n6c (linoleic acid, LA) identified as the sole metabolite showing significant genotype-dependent reduction under 4NQO challenge. cKO mice exhibited downregulated Perilipin-1 and Ki-67, and upregulated FABP5 and E-cadherin. CAV2 knockout also induced lesion acetyl-CoA accumulation and systemic lipid metabolism abnormalities.
CONCLUSIONS: CAV2 knockout inhibits OLK formation and progression by disrupting lipid metabolism homeostasis, including restriction of LA bioavailability. Exogenous fatty acid supplementation failed to rescue OLK progression or restore metabolic homeostasis, highlighting CAV2 as a potential therapeutic target.
METHODS: CAV2 conditional knockout (cKO; CAV2flox/flox; K14-Cre) and control (Flox) C57BL/6 mice were used to establish OLK models via 4-nitroquinoline-N-oxide (4NQO). A subset received a high-fat diet (HFD). Oil red O staining, RNA sequencing, multiplex immunofluorescence (Ki-67, E-cadherin, Perilipin-1, FABP5), ELISA (acetyl-CoA), serum biochemistry (ALT, TG), and targeted GC-MS/MS fatty acid profiling were performed.
RESULTS: CAV2 knockout significantly suppressed OLK progression, evidenced by reduced lesion diameter/number and attenuated pathological severity. HFD failed to rescue OLK progression. RNA-seq confirmed dysregulation of lipid transport, lipolysis, and fatty acid metabolism/biosynthesis. Targeted metabolomics revealed markedly attenuated carcinogen-induced fatty acid accumulation in cKO mice, with C18:2n6c (linoleic acid, LA) identified as the sole metabolite showing significant genotype-dependent reduction under 4NQO challenge. cKO mice exhibited downregulated Perilipin-1 and Ki-67, and upregulated FABP5 and E-cadherin. CAV2 knockout also induced lesion acetyl-CoA accumulation and systemic lipid metabolism abnormalities.
CONCLUSIONS: CAV2 knockout inhibits OLK formation and progression by disrupting lipid metabolism homeostasis, including restriction of LA bioavailability. Exogenous fatty acid supplementation failed to rescue OLK progression or restore metabolic homeostasis, highlighting CAV2 as a potential therapeutic target.