Selenylated Physalis pubescens polysaccharide extends lifespan and activates Nrf2/HO-1-mediated antioxidant defense: structural elucidation and multi-target mechanism.

Through a series of chromatographic purification steps, a novel polysaccharide, PPFP-I, was obtained from Physalis pubescens fruits. Its selenylated derivative (Se-PPFP-I) was synthesized via the HNO3/Na2SeO3 method. Structural characterization indicated that PPFP-I possesses a well-defined backbone composed of →4,6)-β-D-Glcp-(1→, →3,6)-β-D-Glcp-(1 → and →3)-β-D-Glcp-(1 → residues, with five different branched chains. Antioxidant and neuroprotective analyses demonstrated that Se-PPFP-I significantly enhanced superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC), while reducing malondialdehyde (MDA) levels, with these effects being consistent with Nrf2/HO-1 pathway activation. In vivo experiments further showed that Se-PPFP-I markedly improved the survival rate of female Drosophila melanogaster, confirming its lifespan extension efficacy at the organismal level. To elucidate the molecular mechanism underlying these effects, an integrated strategy combining metabolomics, network pharmacology, and molecular docking was employed. Ultra-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS) identified 16 structural fragments derived from Se-PPFP-I. Network pharmacology analysis screened 16 key targets (e.g., STAT3, NFE2L2, and SOD1), and molecular docking further confirmed the stable binding interactions between these metabolites and the core targets. Experimental validation in D. melanogaster revealed that Se-PPFP-I increased the mRNA expression of Nrf2 and HO-1, increased antioxidant enzyme activities (SOD and T-AOC), reduced MDA levels, corroborating the predicted multi-target regulatory network. In conclusion, these findings indicate that Se-PPFP-I extends lifespan, with its effects consistent with Nrf2/HO-1 pathway activation and modulation of multi-target networks, offering a structurally characterized and mechanistically validated candidate for lifespan extension interventions.