(1) Background: The relationship between lipids, apolipoproteins, and telomere length (TL) has been explored in previous studies; however, the causal relationship between the two remains unclear. This study aims to assess the causal relationship between lipids, apolipoproteins, and TL using the two-sample Mendelian randomization (MR) approach; (2) Methods: This study comprehensively employed both univariate MR (uvMR) and multivariate MR (mvMR) methods to genetically evaluate the associations between 21 exposures related to lipids and apolipoproteins and the outcome of TL. During the analysis process, we utilized various statistical methods, including Inverse Variance Weighting (IVW), Weighted Median, MR-Egger regression, MR-PRESSO, and outlier tests. Furthermore, to confirm the robustness of the results, we conducted several sensitivity analyses to explore potential heterogeneity; (3) Results: The uvMR analysis indicated that an increase in MUFA, MUFA/FA ratio, LDL-C, VLDL-C, total cholesterol, ApoB, and triglycerides (TG) was associated with an increase in TL. However, this relationship did not manifest in the mvMR analysis, suggesting that this association may be based on preliminary evidence; (4) Conclusions: MR analysis results suggest potential suggestive positive causal relationships between genetically predicted MUFA, MUFA/FA ratio, LDL-C, VLDL-C, total cholesterol, ApoB, and TG with TL.

Objective: This study aimed to investigate the causal relationship between diabetes mellitus and pathological scarring, including hypertrophic scars (HS) and keloids, and to elucidate the underlying immune cellular mechanisms and key molecular regulators. Methods: We employed a phenome-wide Mendelian randomization approach (MR-PheWAS) to identify potential causal links between diabetes and pathological scars. Separate Mendelian randomization meta-analyses (MR-Meta) were performed for type 1 diabetes (T1D) and type 2 diabetes (T2D). Integrative analyses incorporating single-cell RNA sequencing (scRNA-seq), cell–cell communication inference, metabolic pathway profiling, and transcriptomic differential expression and enrichment analyses were conducted to delineate scar heterogeneity mediated by diabetes-related cellular subpopulations and molecular drivers. Results: MR-PheWAS revealed significant causal associations between HS and multiple diseases. T2D exhibited a positive causal association with HS (OR: 1.13, 95% CI: 1.09–1.17, P < 0.0001), and a negative association with keloids (OR: 0.95, 95% CI: 0.92–0.99, P = 0.016). T1D showed no significant causal relationship with either scar type. Single-cell analysis identified an upregulation of CD4 ⁺ Naive T cells (CD4 ⁺ NT) in HS and a downregulation in keloids. This subset exhibited strong interactions with endothelial cells in both scar types, primarily enriched in the insulin signaling pathway (INS–INSR) signaling axis. Three pivotal genes (GPR35, TMEM91, and ZBTB32) were identified as overlapping molecular links between T2D and pathological scars, all expressed in CD4 ⁺ NT and showing inverse expression trends across HS and keloids. Pseudotime trajectory analysis further revealed divergent expression kinetics of these genes, characterized by early loss and late-phase upregulation. Metabolic pathway analysis implicated these genes in modulating metabolic reprogramming of the CD4 ⁺ NT population, thereby influencing scar differentiation. Conclusion: Convergent multi-omics evidence supports the hypothesis that T2D exerts opposing causal effects on different forms of pathological scarring, potentially mediated through CD4 ⁺ NT. The transcriptomic features, intercellular communication profiles, key gene signatures, and metabolic landscape of this subset collectively suggest that T2D may contribute to divergent fibrotic pathways in HS and keloids via immune microenvironmental modulation.