Systemic metabolic inflammation induced by obesity, diabetes, and gut microbiota dysbiosis further exacerbates testicular dysfunction through the mTOR/HIF-1α signaling axis and the “gut–immune–gonadal axis.” Pharmacological modulation of key immunometabolic regulators, including AMPK, SIRT1, and PPARγ, has been shown to improve sperm quality and hormone levels in experimental models. The gene discussed is HIF1A; the disease is diabetes mellitus.