Identification of Cathepsin H and Metabolic Traits as Potential Biomarkers for Lung Cancer by Mendelian Randomization and Single‐Cell Transcriptomics

Lung cancer is a major global malignancy with debated roles for cathepsin H (CTSH), a lysosomal protease, and underexplored regulation by metabolites. We analyzed lung cancer incidence and hyperglycemia-related mortality trends (1990-2021) using Joinpoint regression. Mendelian randomization (MR), meta-analysis, and two-step mediation examined CTSH and 233 metabolic traits. Single-cell RNA sequencing (scRNA-seq) and TCGA/HPA datasets validated CTSH expression. Lung cancer incidence decreased overall but rose in women, while fasting hyperglycemia-related mortality increased. CTSH elevated lung cancer and adenocarcinoma risks, with docosahexaenoic acid (22:6) and omega-3 fatty acids driving adenocarcinoma progression. A higher linoleic acid (18:2)/total fatty acid ratio reduced risk. scRNA-seq identified CTSH in myeloid cells, especially "mo-Mac," which promoted tumors. CTSH expression patterns were evaluated using TCGA and HPA data, revealing protein-level overexpression in tumors with some divergence from transcriptomic results. CTSH is linked to lung cancer, particularly adenocarcinoma, with modest effects mediated by metabolites like omega-3 fatty acids. Its prominent expression in macrophages suggests novel therapeutic targets. These findings, though consistent, require further validation due to modest effect sizes and dataset heterogeneity.