ET-1 as a Central Regulator of the SAM/SAH Methylation Cycle: A Proposed Unified Mechanism for Metabolic and Neurodegenerative Disease Progression

Chronic elevation of endothelin-1 (ET-1) has been implicated in cardiovascular, renal, and metabolic pathology. We propose that ET-1 may function as a central organizing node in a self-reinforcing pathological loop of a self-reinforcing epigenetic feedback involving the S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) methylation cycle, whose downstream consequences constitute the mechanistic substrate common to obesity, type 2 diabetes, Alzheimer's disease, and malignant transformation. Through oxidative inhibition of S-adenosylhomocysteine hydrolase (SAHH), chronic ET-1 elevation drives SAH accumulation, reduces the SAM/SAH ratio, and impairs methylation of the EDN1 promoter, releasing tonic suppression of ET-1 transcription and closing a pathological loop resistant to single-target intervention. Concurrently, ET-1-driven obstruction of mitochondrial substrate entry forces a shift to anaerobic glycolysis, producing chronic low-grade metabolic acidosis whose physicochemical consequences are distinct from, and more severe than, the nonspecific inflammatory state with which they are conventionally conflated. The severity of phenotypic expression along the resulting disease spectrum is modulated by the degree of MTHFR functional impairment: mild impairment produces the metabolic phenotype of obesity and type 2 diabetes; moderate impairment extends to the neurological phenotype of Alzheimer's disease, driven by ET-1-mediated cerebral vascular obstruction and synaptic calcium channel dysregulation; severe impairment culminates in malignant transformation through irreversible mitochondrial shutdown, global genomic hypomethylation, and failure of apoptotic signaling consistent with the Warburg effect. The intergenerational acceleration of this disease spectrum is explained by rising paternal age at conception increasing germline mutational burden at MTHFR and EDN1 loci, compounded by incomplete epigenetic erasure during gametogenesis transmitting a permissive chromatin state for ET-1 overexpression to successive generations. A multi-target interventional framework targeting ET-1 suppression, SAM/SAH ratio restoration, disruption of the compensatory HPA axis, and mitochondrial recovery is proposed as a mechanistically coherent therapeutic strategy across the full disease spectrum.