Sophocarpine suppresses MAPK-mediated inflammation by restoring gut microbiota in colorectal cancer

Background: Colorectal Cancer (CRC), as one of the most common cancers globally, poses a significant challenge to public health due to its high incidence and mortality rates. This underscores the need for continuous exploration of new therapeutic targets and effective drugs. Sophocarpine (SC), a natural compound derived from traditional Chinese medicine, holds considerable therapeutic potential in the treatment of CRC, however, the relevant mechanisms remains unclear.

Purpose: This study aims to explore the anti-tumor effects of SC against CRC by modulating gut microbiota, and uncover potential mechanisms linking SC's therapeutic effects to gut microbiota regulation by analyzing the impact of SC on microbiota composition and CRC progression.

Material: This study explores the impact of SC on the gut microbiota in CRC by constructing subcutaneous xenograft tumors of CRC and integrating 16S rRNA Sequencing and RNA transcriptomic Sequencing. The fecal microbiota transplantation (FMT) mouse model was used to validate the biological function of SC in correcting gut microbiota dysbiosis to treat CRC. Subsequently, we conducted in vitro studies on the molecular mechanisms by which SC regulates the gut microbiota as an effective hallmark of CRC treatment, using lipopolysaccharide (LPS) to simulate an inflammatory gut microbiota environment and p38 MAPK knockdown cell line.

Results: SC significantly inhibited CRC cell proliferation with IC₅₀ values of 2.547±0.256 μM for HCT116 and 2.851±0.332 μM for LoVo cells. In vivo experiments demonstrated that SC effectively suppressed tumor growth in xenograft models. 16S rRNA Sequencing revealed that SC modulated gut microbiota composition, particularly affecting Bacteroides and Alistipes populations. SC significantly reduced the levels of inflammatory factors and inhibited the MAPK signaling pathway, as evidenced by decreased p-JNK, p-p38 MAPK, and p-NF-κB p65 expression.

Conclusions: Current clinical practice still lacks effective therapeutic agents targeting CRC through gut microbiota modulation. This study presents the first evidence that SC, a natural compound, exhibits dual-action therapeutic efficacy against CRC progression by simultaneously modulating gut microbial composition and suppressing MAPK pathway-mediated inflammatory responses. These findings highlight SC's novel therapeutic potential as a promising microbiota-regulating candidate for CRC intervention, offering an innovative approach that bridges microbial ecology with Cancer signaling pathways.

Colorectal cancer; Gut microbiota; MAPK signaling pathway; Sophocarpine.