Lianhua Qingwen granules biphasically regulate CYP3A4 and mediate metabolic drug interactions via LXRα-interfered dynamic rearrangement of PXR-HSP90α/RXRα/SRC-1 complex.

Lianhua Qingwen granules (LHQW) are widely used to treat acute respiratory infections. Their co-administration with other clinical drugs carries potential risks of metabolic drug interactions (MDIs). This study aimed to clarify the regulatory mechanism of LHQW on cytochrome P450 3A4 (CYP3A4), focusing on LXRα's impact on protein interactions among PXR, HSP90α, RXRα, and SRC-1. The results demonstrated that LHQW exerts temporal biphasic regulation on CYP3A4. A 12-h LHQW treatment promotes PXR-HSP90α binding and the dissociation of the PXR-RXRα/SRC-1 complex, downregulating CYP3A4 expression and elevating systemic exposure to atorvastatin (ATV); this effect can be further potentiated by LXRα activation. In contrast, 72-h treatment promoted PXR-HSP90α dissociation and PXR-RXRα/SRC-1 assembly, facilitating PXR nuclear translocation, upregulating CYP3A4, and accelerating ATV clearance in vivo. Notably, LXRα activation increased cytosolic PXR-HSP90α binding, which hindered PXR-RXRα/SRC-1 complex formation and the nuclear accumulation of PXR, thereby counteracting the 72-h induction of CYP3A4. This effect was abolished by LXRα silencing. These findings reveal that LHQW mediates the temporal biphasic modulation of CYP3A4 and subsequent MDIs via LXRα-driven dynamic rearrangement of the PXR-cofactor complex, providing mechanistic insights for safer polytherapy in clinical practice.