Fengshi Gutong Capsules alleviate aconitums-induced nephrotoxicity via PXR-mediated efflux of aconitum alkaloid

Fengshi Gutong Capsules (FSGT) is widely used for the treatment of rheumatoid arthritis (RA). However, its clinical application is limited because it contains Aconiti Radix Cocta and Aconiti Kusnezoffii Radix Cocta (AA), and the mechanism of compatibility and detoxification remains unclear.

This study was to provide pharmacokinetic and mechanistic insights into the attenuation of AA-induced nephrotoxicity by FSGT compatibility.

Collagen-induced arthritis (CIA) rats were treated with FSGT, its modified formulations (AA or FSGT-AA), or methotrexate, and renal injury was evaluated via biochemical indicators (BUN, CRE, UA) and histopathology. Aconite alkaloids (AC, HA, MA, BAC, BHA, BMA) were quantified in plasma, kidney, and urine by UPLC-MS/MS, while the FBXO44/PXR/P-gp signaling was investigated using Western blotting, immunofluorescence, ubiquitination assays, molecular docking, molecular dynamics simulations, and microscale thermophoresis (MST).

FSGT maintained superior anti-RA efficacy while markedly mitigating AA-induced nephrotoxicity. Pharmacokinetically, FSGT accelerated the clearance and urinary excretion of toxic diester diterpenoid alkaloids, reducing their renal accumulation. Mechanistically, FSGT suppressed E3 ubiquitin ligase FBXO44 expression, inhibited FBXO44-mediated PXR ubiquitination/degradation, promoted PXR expression, and upregulated P-gp efflux transporter expression. Verapamil abolished this protective effect. 18α-glycyrrhetinic acid and kaempferol were confirmed as key active components directly binding FBXO44.

FSGT reduces nephrotoxicity via FBXO44/PXR/P-gp signaling to accelerate toxic aconite alkaloids excretion, providing a scientific basis for "detoxification by compatibility" and preclinical mechanistic support for the safety profile of FSGT.