Syringaresinol Attenuates Aging-Associated Ferroptosis-Relevant Stress Through an HIF-1α-GPX4 Defense Axis

Ferroptosis contributes to aging-associated functional decline, yet compounds with robust organismal efficacy and defined upstream regulatory mechanisms remain limited. Here, we established a diethyl maleate (DEM)-induced glutathione depletion model in wild-type (N2) Caenorhabditis elegans as a survival-based screening platform and identified syringaresinol (Syr) as a leading hit from an in-house small-molecule library. In nematodes, Syr improved survival under DEM challenge, reduced lipid peroxidation, reactive oxygen species (ROS), and malondialdehyde levels, and alleviated age-associated oxidative lipid stress and iron imbalance during natural aging, accompanied by extended lifespan and improved healthspan-related phenotypes. In primary human foreskin fibroblasts, Syr conferred dose-dependent protection against RSL3- or erastin-induced ferroptosis, preserved cellular integrity, suppressed lipid peroxidation and ROS, and restored expression of GPX4, SLC7A11, and ferritin. In two senescence models, Syr also attenuated senescence-associated phenotypes and ferroptosis-related oxidative lipid stress, concomitant with recovery of GPX4 expression. Network-based prediction and functional perturbation identified HIF-1α as a candidate mediator of Syr-associated cytoprotection. HIF-1α knockdown weakened Syr-mediated protection and largely prevented GPX4 restoration, whereas GPX4 knockdown did not alter HIF-1α abundance. These findings support a functional HIF-1α-GPX4 defense axis in fibroblasts, while direct transcriptional regulation remains to be clarified. Overall, Syr attenuates ferroptosis-relevant oxidative lipid stress and aging-associated phenotypes in C. elegans and human fibroblast models, supporting further mechanistic and mammalian in vivo validation.