Exploring the laxative effects of emodin on constipation through chloride channel activation

Constipation, a prevalent gastrointestinal disorder, significantly impairs quality of life. Emodin, a bioactive anthraquinone found in traditional herbal remedies like Rheum palmatum, is empirically known for its laxative effects, yet its precise molecular mechanism remains incompletely understood. This study aimed to elucidate the laxative potential of emodin and delineate its underlying mechanism, with a specific focus on the activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. This therapeutic effect was abrogated in W1282X cystic fibrosis mice lacking functional CFTR, demonstrating CFTR-dependency. In HT-29 human colonic epithelial cells, emodin activated the CFTR chloride channel detected by a fluorescence-based membrane potential assay in a concentration-dependent manner with a half-maximal effective concentration (EC₅₀) of 10⁻⁵·⁷ M and a maximal effect reaching 68.3% of that induced by the positive control, genistein. Mechanistic investigations revealed that emodin did not alter the total protein abundance of CFTR but significantly enhanced its phosphorylation. Pharmacological inhibition of the cAMP/protein kinase A (PKA) pathway attenuated emodin-induced CFTR activation and laxative effects. Consistently, emodin upregulated the mRNA expression of key cAMP/PKA pathway components, PRKACB and CREB1. In conclusion, our findings demonstrate that emodin alleviates constipation by activating the CFTR chloride channel. This effect is mediated through the cAMP/PKA signaling pathway, which enhances CFTR phosphorylation and channel activity, thereby promoting chloride-dependent fluid secretion into the colonic lumen. This study clarifies a pivotal molecular mechanism for emodin's laxative action and supports its therapeutic potential.