Jianpi‐Huogu Prescription Repairs Nontraumatic Osteonecrosis of the Femoral Head by Inhibiting NAMPT/STK11/HMGCR/ACAT1 Axis‐Mediated Lipid Production

Jianpi‐Huogu Prescription (JHP), integrating the classic Chinese herbal formulas Linggui‐Zhugan Decoction and Si‐Wu Decoction, has shown clinical efficacy in treating early nontraumatic osteonecrosis of the femoral head (NONFH). In this study, 299 chemical constituents of JHP were identified using ultra‐performance liquid chromatography–quadrupole‐time of flight mass spectrometry. Pharmacological evaluations in rats with early NONFH demonstrated that JHP attenuated femoral head pathological changes, improved gait parameters, increased mechanical pain thresholds, reduced serum levels of triglycerides, total cholesterol, low‐density lipoprotein, very‐low‐density lipoprotein, and the TXB₂/6‐keto‐PGF₁α ratio while elevating high‐density lipoprotein, decreased serum inflammatory cytokines (IL‐1β, IL‐6, TNF‐α) and the RANKL/OPG ratio, and restored bone trabecular morphology and reduced the number of bone marrow adipocytes. Mechanistically, through transcriptomic profiling, network calculations and experimental validation, JHP downregulated NMNAT1, NMNAT3, and NAMPT in the femoral head, thereby reducing NAD + synthesis, increased ATP production (evidenced by a decreased ADP/ATP ratio) and upregulated STK11 expression, activated p‐HMGCR while suppressing ACAT1 thus inhibiting cholesterol synthesis and lipid accumulation, and surface plasmon resonance confirmed direct binding of its active components (ligustilide, 5,6,4′‐trihydroxy‐7,3′‐dimethoxyflavone, (Z)‐3‐butylidenephthalide, senkyunolide H, ferulic acid, guanosine) to NMNAT1. In conclusion, JHP ameliorates early NONFH by regulating lipid metabolism, improving hypercoagulability, and restoring bone homeostasis through the NMNAT1/NMNAT3/NAMPT/STK11/HMGCR/ACAT1 axis.