Duhuo Jisheng Decoction Mitigates Intervertebral Disc Degeneration Via Metabolic Reprogramming and TGF-β/Smad-Driven Autophagy-Fibrosis Network Modulation.

Duhuo Jisheng Decoction (DHJSD) shows promise for treating intervertebral disc degeneration (IVDD), but its mechanisms concerning autophagy and fibrosis are unclear. Using network pharmacology, metabolomics, UHPLC-Q-TOF/MS, and functional studies (in vitro and in vivo), we systematically explored DHJSD's molecular mechanisms. DHJSD has 254 constituents; those may regulate inflammation, apoptosis, and metabolic processes. DHJSD attenuates ECM/fibrosis-related changes, lowers BMP2 expression, is associated with reduced TGF-β/Smad2/3 phosphorylation, and partially improves annulus fibrosus morphology. SB431542 attenuated IL-1β-induced TGF-β pathway activation and BMP2 expression, supporting the involvement of this pathway in DHJSD-related regulation of fibrosis markers. The levels of serum IL-1β and TNF-α significantly decreased in animal models. Through glycerophospholipid and sphingolipid metabolism, DHJSD reshapes lipid homeostasis and may be associated with reduced TGF-β overactivation by downregulating pro-fibrotic compounds and upregulating anti-inflammatory metabolites. DHJSD modulates autophagy-related markers via controlling the LC3-II/LC3-I ratio and BCL2, P62 expression. DHJSD may affect glycolysis-related and oxidative phosphorylation-related changes and may be associated with phosphatidylcholine/ethanolamine-related mitochondrial membrane changes. DHJSD treats IVDD via a "metabolic reprogramming-TGF-β-related regulation-autophagy/mitochondrial-related remodeling" network, suggesting a potential multi-target strategy and demonstrating the value of multi-omics in analyzing traditional medicine.