Targeting PKM2 and GAPDH by baicalein and corilagin from TCM reduces lactylation and enhance cisplatin sensitivity in lung cancer.

Protein lactylation plays a key role in cancer progression and chemotherapy sensitivity. Glycolysis inhibitors offer promise, particularly through combination strategies to counter metabolic compensation. This study aims to identify glycolysis-targeting active ingredients from Traditional Chinese Medicine (TCM) and to investigate their enhanced effect in reducing lactylation to inhibit lung cancer. We first screened heat-clearing and detoxifying TCM herbs based on their effects on lactate levels, and then we developed a lactate-producing key enzyme protein stability chip (L-PTSC) to further screen the selected herbs and identify their targets. Through semi-preparative separation of herbal extracts, we identified the active components and characterized their target interactions. Finally, the efficacy of the triple combination (baicalein + corilagin + cisplatin) was validated in multiple lung cancer models, including cell lines, resistant lines, organoids, and xenografts. Extracts from Scutellaria baicalensis (SBG) and Geranium wilfordii (GWM) significantly inhibited glycolysis. Baicalein (from SBG) and corilagin (from GWM) were identified as candidate of PKM2 and GAPDH binders through l-PTSC. Given the central role of PKM2 and GAPDH in glycolysis, we systematically evaluated the enhanced antitumor effects of baicalein and corilagin using the Combination Index (CI) method via CompuSyn software (Chou-Talalay approach). Mechanistic investigations revealed that the triple combination treatment associated with lowered global protein lactylation levels, with AARS1 and MRE11 being particularly affected. This study established a natural product-based targeting strategy, identifying baicalein and corilagin from TCM herbs that engage PKM2 and GAPDH, and are associated with reduced lactylation and enhanced cisplatin sensitivity in lung cancer.