Cancer cachexia — the devastating muscle-wasting syndrome affecting up to 80% of advanced cancer patients — remains one of oncology's most treatment-resistant problems, directly shortening survival and reducing quality of life. New mechanistic evidence linking a centuries-old Chinese herbal formula to a specific epigenetic pathway in immune cells offers a fresh angle on this unmet clinical challenge, and potentially implicates lactate metabolism as a therapeutic target worth pursuing beyond the formula itself.
Sijunzi decoction (SJZD), a classical four-herb combination used in Traditional Chinese Medicine, was tested in two mouse models of cancer cachexia — KPC pancreatic and MC38 colon cancer — and demonstrated measurable preservation of body and muscle weight alongside downregulation of the atrophy markers Atrogin-1, Myostatin, and MuRF1. The mechanism traced through tumor-associated macrophages (TAMs): SJZD suppressed lactate uptake via monocarboxylate transporter 1 (MCT1), reducing intracellular lactate accumulation and, critically, decreasing histone H3K18 lactylation — an epigenetic modification that drives M2 macrophage polarization. M2-polarized TAMs are known promoters of an immunosuppressive, pro-cachectic tumor microenvironment. Systemic inflammatory cytokines TNF-α and IL-6 fell in tumor, serum, and muscle compartments. Genetic knockdown of MCT1 in TAMs confirmed the pathway's causal role in vitro.
This study's most intellectually significant contribution is the connection between lactate-driven histone lactylation and TAM polarization in cachexia — a relatively novel epigenetic mechanism first described in macrophages only around 2019. Placing SJZD within this framework bridges ethnopharmacology and cutting-edge chromatin biology. That said, several caveats deserve emphasis: both models are murine, and mouse cachexia biology diverges meaningfully from human disease; the active constituents of SJZD responsible for MCT1 inhibition remain incompletely characterized despite LC-MS profiling; and dose translation to humans is not straightforward. The study is also mechanistically dense but lacks survival endpoints. As a single preclinical study, it is hypothesis-generating rather than practice-informing. Still, the MCT1/H3K18 lactylation axis in TAMs now emerges as a pharmacologically tractable target worthy of dedicated drug-discovery efforts independent of the herbal source.
