γ-Tocopherol attenuates COPD-associated macrophage inflammation through the PSEN1–SYT7–PI3K/Akt axis

Rationale: Chronic obstructive pulmonary disease (COPD) features persistent airway inflammation, oxidative/nitrative stress, and macrophage activation. γ-tocopherol has antioxidant and anti-inflammatory activity, but its disease relevance and molecular targets are unclear. Objectives: To test whether γ-tocopherol attenuates disease-associated inflammation and define the macrophage mechanism. Methods: Multi-omics integrated analysis combined with γ-tocopherol-treated COPD-like mouse models was performed to evaluate the anti-inflammatory effects of γ-tocopherol and identify its target cell populations. Furthermore, target prediction, cellular thermal shift assay, co-immunoprecipitation, and other experimental approaches were used to identify the molecular target of γ-tocopherol and elucidate the downstream mechanisms underlying its anti-inflammatory and antioxidant effects. Measurements and Main Results: COPD was associated with altered γ-tocopherol metabolism and vitamin E-related transcriptional programs. γ-tocopherol reduced inflammatory cell accumulation, nitric oxide metabolites, macrophage activation, and lung inflammation in COPD-like mouse models. Alveolar macrophages were identified as the primary target cell population of γ-tocopherol in lung tissue. γ-tocopherol treatment suppressed nitric oxide synthesis and inflammatory cytokine release in macrophages, and this effect depended on the engagement of γ-tocopherol with PSEN1. Further mechanistic analysis identified SYT7 as a downstream effector of PSEN1, linking γ-tocopherol treatment to reduced PI3K/AKT signaling activity and attenuated inflammatory readouts. Conclusions: γ-tocopherol attenuates macrophage-centered inflammation in COPD-like models through a PSEN1–SYT7–PI3K/AKT signaling axis.