Work

Rigosertib promotes expression of the antimicrobial peptide beta-defensin-3 in human cells

Year: 2026

Type: article

Abstract: Antimicrobial defense in the human gut relies on innate immune recognition of microbes via pattern recognition receptors, triggering antimicrobial peptide (AMP) expression and immune cell recruitment. Among AMPs, beta-defensins are crucial defense effectors, exhibiting broad-spectrum antimicrobial activity and immunomodulatory functions. Their inducible expression makes them attractive targets for therapeutic modulation, particularly given the growing threat of antimicrobial resistance. Through the evaluation of clinically approved or investigational compounds, we identified the multi-kinase inhibitor Rigosertib as an inducer of the human beta-defensin-3 (HBD3) in colon epithelial cell lines and in organoids. Notably, Rigosertib robustly induced HBD3 even at the lowest concentration tested in vitro, whereas proinflammatory cytokine expression increased only at the highest concentration and to a substantially lesser extent. Mechanistically, Rigosertib-triggered induction of HBD3 expression was found to be primarily dependent on the epidermal growth factor receptor (EGFR) and downstream P38 pathway, with ERK1/2 and JNK contributing to a lesser extent. Functionally, Rigosertib enhanced the antimicrobial activity of colon-derived cells and organoids against intestinal bacterial pathogens. Moreover, Rigosertib induced AMP expression in a range of non-intestinal cells from different tissues, including hepatic cells. Collectively, these findings support the potential of Rigosertib to enhance endogenous antimicrobial defense while limiting excessive and potentially detrimental inflammatory responses.

Source: Scientific Reports

DOI: 10.1038/s41598-026-79053-5