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. A 220‐compound screen in DEM‐challenged C. elegans identified syringaresinol (Syr) as a lead protective compound. Syr alleviated aging‐ and ferroptosis‐associated phenotypes in C. elegans and human foreskin fibroblasts by reducing lipid peroxidation, ROS accumulation, MDA levels, labile Fe 2+ , cell death, and SA‐β‐gal activity, while restoring GPX4/SLC7A11/ferritin‐associated defense responses. The proposed mechanism suggests that Syr attenuates senescence‐associated functional decline through a HIF‐1α‐associated GPX4 protective axis. The dashed arrow denotes a hypothesized mediator or interaction that remains to be experimentally validated.