Upstream drivers, chronic hyperglycemia, hemodynamic overload, dyslipidemia/lipotoxicity, AGEs (“metabolic memory”), microvascular stress, and sterile/viral inflammation, converge on signaling hubs, including mTORC1, ER stress/UPR and autophagy/TFEB, TXNIP, EGFR → p70S6K/RPS6, ERK/VEGF, TGF-β/EMT/Notch, ROCK, HDAC4 → calcineurin, complement C3a/C3aR, and NLRP3/pyroptosis (TRAIL–DR5), as well as epigenetic/RNA programs. This evidence concerns the gene RPS6 and metabolic syndrome.