SDF2L1 modulates oxLDL-induced endoplasmic reticulum stress, protein aggregation, and O-mannosylation in myocardial infarction and lung cancer

Oxidized low-density lipoprotein (oxLDL), formed by LDL oxidative modification, drives pathogenesis in cardiovascular diseases and cancers through ER stress, inflammation, and protein aggregation. Stromal-derived factor 2-like 1 (SDF2L1), an ER-resident chaperone, may modulate these processes, but its role in oxLDL-related pathologies remains unclear. We analyzed spatial transcriptomic datasets from human myocardial infarction (MI) and lung cancer tissues. In vitro, we generated stable SDF2L1 knockdown (KD) or overexpression (OE) models in EA.hy926 endothelial and A549 lung epithelial cells, treated with oxLDL (10 μg/mL, 48 h). In vivo, we created global Sdf2l1 knockout (Sdf2l1−/−) mice via CRISPR-Cas9 and administered oxLDL (1.4 mg/kg i.v., 7 days). Assessments included Western blotting for ER stress markers, qPCR for inflammatory genes, PROTEOSTAT assays for protein aggregates, ELISA for O-mannosyltransferase levels, and LC–MS/MS glycoproteomics for O-mannosylation profiles. Spatial transcriptomics revealed elevated SDF2L1 in MI ischemic zones and lung cancer tissues, correlating with ATF6 (ER stress) and OLR1 (oxLDL receptor). In cells, both SDF2L1 KD and OE paradoxically exacerbated oxLDL-induced ER stress (elevated p-PERK, p-IRE1α, spliced XBP1, cleaved ATF6), inflammation (NF-κB, IL-6, NLRP3 upregulation), and protein aggregation. Sdf2l1−/− mice showed heightened oxLDL-induced ER stress, inflammatory cytokines (Il-1β, Il-6, Tnf), histopathological changes (mucous degeneration, infiltration), and early disease biomarkers (e.g., Slc7a7 for MI, Kras for lung cancer). Mechanistically, SDF2L1 levels positively regulated O-mannosyltransferase content; Sdf2l1 deficiency reduced these enzymes and altered protein O-mannosylation, increasing TLR4 and MCM8 modifications/protein levels in vivo, while OE decreased them in vitro. SDF2L1 exerts a complex modulatory role in oxLDL responses, linking ER stress, protein aggregation, and O-mannosylation to MI and lung cancer. Optimal SDF2L1 levels maintain homeostasis; deviations promote pathology, positioning SDF2L1 as a potential biomarker and therapeutic target for oxLDL-driven diseases.