ALAS1 catalyzes the pyridoxal 5'-phosphate-dependent condensation of succinyl-CoA and glycine to form 5-aminolevulinic acid, the first committed step of hepatic heme biosynthesis. The enzyme is subject to feedback inhibition by heme, which downregulates both mRNA stability and protein levels. Recent evidence suggests ALAS1 has a noncanonical cytoplasmic role as a heme-independent repressor of small RNA-mediated gene silencing, independent of its canonical mitochondrial function 1. ALAS1 dysregulation is central to acute hepatic porphyria pathogenesis: upregulation leads to toxic accumulation of 5-aminolevulinic acid and porphobilinogen, triggering acute neurovisceral attacks. Givosiran, an FDA-approved small interfering RNA that inhibits ALAS1 expression, significantly reduces attack rate and disease burden in acute intermittent porphyria 2. In a phase 3 trial of 94 patients with acute hepatic porphyria, givosiran reduced the annualized attack rate by 74% compared to placebo, lowered urinary aminolevulinic acid and porphobilinogen levels, and decreased hemin use 2. However, givosiran therapy is associated with hepatic and renal adverse events, including serum aminotransferase elevations and changes in creatinine and glomerular filtration rate 2. Givosiran has also been investigated as an adjuvant for other siRNA therapies, given that ALAS1 suppression enhances siRNA-mediated knockdown 1.