Atractylodes chinensis polysaccharides downregulate RHEB to confer splenoprotective effects against aging-associated disorders.

Population aging represents a major global health challenge, highlighting the need for interventions that target fundamental aging mechanisms. The spleen, a central organ in both traditional medicine and systemic immunity, undergoes functional decline with age. The present study investigated the splenoprotective effects and underlying mechanisms of Atractylodes chinensis polysaccharides (ACP) in aging from the perspective of targeted regulation. In aged mice, ACP treatment attenuated splenic apoptosis and decreased the expression of the pro-inflammatory mediators TNFAIP2 and CXCR3. Integrative proteomic and transcriptomic profiling identified the small GTPase RHEB as a critical regulatory hub. Mechanistically, ACP treatment downregulated expression of RHEB involved to the mTORC1 pathway with notable statistical significance at the protein level. Structural and molecular docking analyses revealed high cross-species conservation of RHEB and stable binding between ACP monosaccharides and both RHEB and specific E3 ubiquitin ligases RNF185 and RNF121. The molecular glue property further accounted for the downregulation of RHEB protein, which is mediated by ubiquitination and degradation. In vitro, ACP treatment mirrored the effects of RHEB knockdown, resulting in reduced reactive oxygen species accumulation and senescence-associated β-galactosidase activity. Integrative analysis between proteomics data and clinical lymphoma data of spleen revealed that ACP reversed the age-associated expression of genes linked to senescence and tumorigenesis (ASPM, SKA1, and FOXO1). Collectively, these findings indicate that ACP alleviates splenic aging by targeting RHEB and modulating apoptosis, inflammatory events, oxidative stress, and the cellular senescence phenotype, thereby providing a mechanistic foundation for developing ACP-based strategies to protect the spleen through delayed aging.