Flavonoid Extract of <i>Senecio scandens</i> Buch.-Ham. Ameliorates CTX-Induced Immunosuppression and Intestinal Damage via Activating the MyD88-Mediated Nuclear Factor-κB Signaling Pathway.

Abstract

<b>Background/Objectives:</b><i>Senecio scandens</i> Buch.-Ham. is a flavonoid-rich traditional medicinal plant with established immunomodulatory properties. However, the mechanisms underlying the immunoregulatory and intestinal protective effects of its flavonoid extract (<i>Senecio scandens</i> flavonoids-SSF) remain unclear. This study characterized SSF's bioactive components and evaluated its efficacy against cyclophosphamide (CTX)-induced immunosuppression and intestinal injury. <b>Methods:</b> The constituents of SSF were identified using UHPLC/Q-Orbitrap/HRMS. Mice with CTX-induced immunosuppression were treated with SSF (80, 160, 320 mg/kg) for seven days. Immune parameters (organ indices, lymphocyte proliferation, cytokine, and immunoglobulin levels) and gut barrier integrity markers (ZO-1, Occludin, Claudin-1 protein expression; sIgA secretion; microbiota composition) were assessed. Network pharmacology combined with functional assays elucidated the underlying regulatory mechanisms. <b>Results:</b> Twenty flavonoids were identified in SSF, with six prototype compounds detectable in the blood. The SSF treatment significantly ameliorated CTX-induced weight loss and atrophy of the thymus and spleen. It enhanced splenic T- and B-lymphocyte proliferation by 43.6% and 29.7%, respectively; normalized the CD4⁺/CD8⁺ ratio (1.57-fold increase); and elevated levels of IL-2, IL-6, IL-10, TNF-α, IFN-γ, IgM, and IgG. Moreover, SSF reinforced the intestinal barrier by upregulating tight junction protein expression and sIgA levels while modulating the gut microbiota, enriching beneficial taxa (e.g., the <i>Lachnospiraceae_NK4A136_group</i>, <i>Akkermansia</i>) and suppressing pathogenic <i>Alistipes</i>. Mechanistically, SSF activated the TLR/MyD88/NF-κB pathway, with isoquercitrin identified as a pivotal bioactive constituent. <b>Conclusions:</b> SSF effectively mitigates CTX-induced immunosuppression and intestinal damage. These findings highlight SSF's potential as a dual-functional natural agent for immunomodulation and intestinal protection. Subsequent research should validate isoquercitrin's molecular targets and assess SSF's clinical efficacy.