Duhuo Jisheng Decoction Mitigates Intervertebral Disc Degeneration via Metabolic Reprogramming and TGF‐β/Smad‐Driven Autophagy‐Fibrosis Network Modulation

ABSTRACT

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.