Phosphoethanolamine: a translational journey from biological process and physiopathological effects to therapeutical...

Phosphoethanolamine (pETN), an endogenous metabolite in the Kennedy pathway for membrane phospholipid synthesis, can be chemically synthesized and exemplifies translational pharmacology through its journey from basic biochemistry to clinical application. Initially recognized for phosphatidylethanolamine biosynthesis via PCYT2-mediated conversion, pETN gained clinical attention following reports of Brazilian cancer patients with pETN-containing products. Subsequent pharmacological studies revealed favorable safety profiles in preclinical and clinical settings, with oral bioavailability of 6%-7%. Mechanistic investigations identified pETN as a competitive inhibitor of succinate dehydrogenase (complex II and Krebs cycle), providing molecular rationale for its mitochondrial effects. This discovery opened new therapeutic avenues beyond oncology, particularly in ischemia-reperfusion injury, where pETN's succinate dehydrogenase inhibitory activity could mitigate pathological succinate accumulation and subsequent oxidative damage during reperfusion. The translational trajectory of pETN, from endogenous metabolism through clinical observation to mechanistic understanding, exemplifies the bidirectional nature of modern pharmacological research and positions this naturally occurring compound as a promising therapeutic candidate for mitochondrial dysfunction-related conditions.