Abstract

Ethnopharmacological relevance Sanghuangporus vaninii (SH) is a medicinal mushroom used in traditional Chinese medicine to treat conditions described in ancient texts as “Zheng Jia Ji Ju” and “Xue Li”. These terms are understood to be analogous to tumors and hematochezia, respectively. Nevertheless, the therapeutic potential and precise mechanisms of SH in inhibiting colitis-associated malignant transformation remain to be elucidated. Aim of the study This study aimed to evaluate the antitumor effect of SH on colitis-associated colorectal cancer (CAC) and to delineate the fundamental mechanisms. Materials and methods The therapeutic efficacy of SH was validated using an AOM/DSS-induced CAC mouse model. Cytokine levels were quantified by ELISA. To identify the potential targets of SH, a network pharmacology approach was utilized. Subsequently, in vitro assays assessed the effects of SH on the viability, colony formation, along with cell cycle distribution of colorectal cancer (CRC) cells. A macrophage-CRC cell co-culture system was established to model an inflammatory microenvironment. The molecular mechanisms were elucidated through a series of assays, including flow cytometry, immunohistochemistry (IHC), immunofluorescence (IF), western blotting (WB), RT-qPCR, and co-immunoprecipitation (Co-IP). Results SH treatment dose-dependently suppressed colitis-associated carcinogenesis in AOM/DSS mice, improving body weight, colon length, and survival, while reducing tumor number and disease activity index. In colon tissues and serum, SH rebalanced the cytokine profile by suppressing positive regulators of inflammation (IL-6, IL-1β, TNF-α) and enhancing negative regulators of inflammation (IL-10, TGF-β). Network pharmacological analysis identified the PPARγ/NF-κB axis as the core pathway. This was validated in vitro and in vivo , where SH inhibited CRC cell proliferation, triggered cell cycle arrest, and promoted macrophage polarization towards an anti-inflammatory a