Precision metabolic therapy for propionic acidemia.

Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by a deficiency of mitochondrial propionyl-CoA carboxylase, leading to the accumulation of propionyl-CoA and toxic metabolites that disrupt TCA cycle flux and ammonia detoxification. Propionyl-CoA is generated from gut microbiome-derived propionate, propiogenic amino acids, odd-chain fatty acids, and cholesterol side chains. Its accumulation produces downstream metabolites such as propionylcarnitine and methylcitrate and promotes histone propionylation. These alterations collectively contribute to mitochondrial dysfunction, oxidative stress, and multi-organ pathology. Current clinical management focuses on reducing propionyl-CoA burden through dietary restriction and supportive therapies, but long-term outcomes remain suboptimal due to poor tolerability and progressive complications. Although liver transplantation improves hepatic metabolism, it does not fully correct extrahepatic disease. Gene-based approaches, including mRNA-based enzyme replacement and viral vector-mediated gene delivery, show promise but face challenges related to delivery efficiency, durability of expression, and immune responses. Emerging small-molecule strategies aim to reprogram metabolism by restoring the balance between propionyl-CoA and acetyl-CoA while replenishing cellular CoA pools. Precision metabolic therapy may combine acetate supplementation and NRF2 activation to enhance acetyl-CoA production and mitochondrial resilience, while suppressing propionyl-CoA formation through ACSS3 inhibition and propiogenic amino acid restriction. In parallel, CoA availability may be increased through activation of PANK1-3, inhibition of PANK4, and supplementation with CoA precursor compounds. We propose that rational combination therapy targeting multiple nodes of short-chain fatty-acid metabolism and CoA homeostasis will provide a more effective strategy than single-agent approaches for correcting metabolic imbalance in PA.