CD4 and Other metabolic disease: MHC class II protein expression deficiency would cause a compromise of CD4+ T cell development and increased autoimmunity, thereby leading to suboptimal T cell response and severe immunodeficiency (Chen et al., 2017; Santambrogio, 2022) These findings could be linked with the significantly enriched autoimmune thyroid disease pathway, as autoimmune and metabolic disorders are important non-genetic risk factors for POF patients (Chon, Umair & Yoon, 2021).