Table 2_Kazachstania pintolopesii accelerates splenic senescence in aged mice via immune cell reprogramming, immunosenescence and amelioration by Astragaloside IV.xlsx

Histopathological staining including H&E, Masson, Prussian blue, and IHC staining was performed to visualize splenic structural impairment, fibrosis, iron deposition, and target protein expression. Bioinformatics analyses containing UMAP dimensionality reduction, pseudotime trajectory analysis, DEG screening, and GO/KEGG functional enrichment were conducted to dissect key molecular pathways.</p>Results<p>The results showed that K. pintolopesii induced characteristic splenic structural changes in aged mice, including white pulp lymphocyte rarefaction, mild interstitial fibrosis, and prominent iron overload, accompanied by immune subset remodeling.

Mechanistically, K. pintolopesii promoted the differentiation of naive T cells into effector/memory phenotypes, drove B cell polarization toward a pro-senescent marginal zone signature, and elicited myeloid cell reprogramming with activated ferroptosis. These pathological events originated from the synergistic crosstalk between ferro-aging (iron overload and ACSL4-mediated lipid peroxidation) and chronic inflammation. Moreover, AGS intervention significantly attenuated KP-associated pathological changes by restoring splenic immune function, modulating iron metabolism and redox homeostasis, suppressing ferroptosis/ferro-aging signaling, and disrupting the senescence-inflammation positive feedback loop.</p>Discussion<p>In conclusion, K. pintolopesii exacerbates splenic senescence in aged mice via the synergistic interaction between immune senescence and ferro-aging.

AGS exerts protective effects on the spleen by targeting the iron-immune axis. This study demonstrates that AGS is a promising therapeutic candidate for the intervention of aging-associated splenic immune dysfunction, providing novel insights into the mechanism of fungal-induced splenic senescence and potential anti-aging therapeutic strategies.</p>