Sijunzi decoction alleviates cancer cachexia myatrophy by suppressing M2 polarization of tumor-associated macrophages via the MCT1/lactate/H3K18 lactylation pathway.

[ETHNOPHARMACOLOGICAL RELEVANCE] Chinese expert consensus shows that Sijunzi decoction (SJZD) can improve cancer cachexia myatrophy (CCMA) in clinical, but its mechanism remains unclear.

[AIM OF THE STUDY] To explore the effects of SJZD on tumor-associated macrophages (TAMs) polarization via the monocarboxylate transporter 1 (MCT1)/lactate/histone H3K18 lactylation (H3K18Lac) pathway, thereby improving CCMA.

[MATERIALS AND METHODS] KPC pancreatic and MC38 colon cancer cachexia mice models were constructed to evaluate the therapeutic effects of SJZD on CCMA, including body weight, muscle weight, muscle fiber condition and myatrophy markers (Atrogin-1, Myostatin, MuRF1). The regulatory effects of SJZD on systemic inflammation were evaluated, including TNF-α and IL-6 levels in tumors, serums, and muscles. TAMs polarization and the MCT1/lactate/H3K18Lac pathway were analyzed in vivo and in vitro using flow cytometry and western blot. Genetic manipulation of MCT1 in TAMs was employed for mechanistic validation in vitro. The main components of SJZD and SJZD containing serum were identified by liquid chromatography-mass spectrometry analysis.

[RESULTS] SJZD, particularly at a medium dose, significantly alleviated the loss of body weight and muscle weight, downregulated myatrophy markers, reduced systemic levels of TNF-α and IL-6 in vivo. SJZD decreased lactate accumulation and downregulated MCT1 and H3K18Lac expression in TAMs, ultimately inhibited M2 polarization of TAMs. MCT1 knockdown also decreased the levels of lactate, H3K18Lac and M2 polarization in TAMs. Recovery of MCT1 expression after SJZD containing serum intervention could counteract the regulatory effects of SJZD on lactate-H3K18Lac-M2 polarization axis in TAMs.

[CONCLUSION] This study demonstrated that SJZD alleviated CCMA by inhibiting the MCT1/lactate/H3K18Lac pathway to reduce the M2 polarization of TAMs. The elucidation of the pharmacological mechanism of SJZD provided a scientific rationale for its application in CCMA treatment.