Inflammation related proteins and PLCG1 may contribute to papillary thyroid carcinoma risk through a potential regulatory axis

Papillary thyroid carcinoma (PTC) is usually indolent, but a subset of patients shows aggressive behavior. Understanding protein-level mechanisms is essential for identifying new therapeutic targets. We integrated protein quantitative trait loci (pQTL)-based Mendelian randomization (MR), transcriptomic validation, and mediation analysis to investigate protein-level causal pathways in PTC. Genome-wide association study (GWAS) summary statistics for PTC were obtained from the FinnGen cohort (2400 cases, 78,749 controls). Candidate proteins were selected based on prior evidence of involvement in pyroptosis-related pathways, including phospholipase C gamma 1 (PLCG1), which has been functionally linked to inflammation-associated cell death. pQTL data were sourced from the UK Biobank (UKB) and deCODE datasets. Two-sample MR was conducted using the inverse variance weighting (IVW) method, with sensitivity analyses for pleiotropy and heterogeneity. Mediation analysis was used to estimate indirect effects of upstream proteins on PTC risk via PLCG1. Differential expression was assessed using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project via the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) platform. Among 11 pyroptosis-related proteins with available pQTL instruments, the genetically predicted plasma level of phospholipase C gamma 1 (PLCG1) was significantly associated with reduced PTC risk (OR = 0.679, 95% CI 0.520–0.887, p = 0.004). Its downregulation in tumor tissues was confirmed by RNA-sequencing data from TCGA-THCA (p < 0.001). We next performed MR using data from the UKB-PPP, identifying 118 proteins with FDR-significant causal associations with PTC risk (FDR < 0.1), including 58 protective and 60 risk-enhancing proteins. Of the 118 proteins, 28 were causally associated with PLCG1 expression, with inflammation-related proteins comprising the largest proportion (46.4%). Mediation analysis revealed that SMPD3 (25.21%, p = 0.008), SIRT1 (22.70%, p = 0.007), and PPM1B (19.91%, p = 0.005) exerted significant indirect effects on PTC risk via PLCG1. These proteins were also downregulated in tumor tissues, with SMPD3 showing the most pronounced decrease (log₂FC = − 1.303, adjp = 3.63 × 10−127). Our study findings suggest a potential regulatory axis in which inflammation-related proteins, such as SMPD3, may influence the risk of papillary thyroid carcinoma (PTC) through the pyroptosis-associated mediator PLCG1. These associations suggest a possible protein-level pathway in PTC, with SMPD3 and PLCG1 as promising molecular candidates, although further experimental validation is required to confirm their functional roles.