Multiomics analysis revealed the regulatory role of chenodeoxycholic acid in fatty acid metabolism and lipid homeostasis.

OBJECTIVE: This study aimed to investigate the regulatory role and mechanisms of chenodeoxycholic acid (CDCA) on lipid metabolism, and to evaluate its therapeutic potential in lipid metabolism-related diseases such as acne, seborrheic alopecia, and prostate cancer, with the aim of identifying safer and more sustainable treatment alternatives. METHODS: Lipid-overproduction models were established using RM-1 (murine prostate cancer cells) and primary sebaceous gland cells, stimulated by linoleic acid (LA) and dihydrotestosterone (DHT), respectively. CDCA's mechanisms were explored using transcriptomics, proteomics, and fatty acid-targeted metabolomics. In vivo validation was conducted via intradermal injection of CDCA into the sebaceous gland area of golden hamsters to assess its effect on sebaceous lipid metabolism. RESULTS: CDCA significantly reduced intracellular lipid accumulation in both murine prostate cancer cells (RM-1) and primary sebaceous gland cells, and suppressed the expression of the androgen receptor (AR), along with the downregulation of key lipogenic enzymes (SREBF1, FASN, FADS2). Mitochondrial membrane potential was restored in CDCA-treated cells. Multi-omics analyses revealed that CDCA modulated fatty acid biosynthesis and degradation, energy metabolism, mitochondrial function, and Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) signaling. Lipidomic profiling demonstrated a shift from saturated to unsaturated fatty acid dominance after CDCA treatment. In vivo, CDCA decreased sebaceous lipid accumulation and downregulated PPAR-γ expression in golden hamsters. CONCLUSION: CDCA exerted multifaceted regulatory effects on lipid metabolism, hormone signaling, and mitochondrial dynamics. These effects contributed to the maintenance of sebaceous gland homeostasis and supported the development of innovative and potentially more biocompatible therapies for lipid-related disorders.