GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE277nnn/GSE277946/primaryOK200TranscriptomicsCaenorhabditis elegansExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE277946GEOGSEfalseReductive death is averted by a conserved de novo lipogenic switchBiguanides, including metformin, the world’s most prescribed oral hypoglycemic, extend health-span and lifespan in vertebrates and invertebrates. Given the widespread use and apparent safety of metformin, it is assumed that its effects are not associated with toxicity, except when in marked excess. Here we determine that accumulation of damaging reducing equivalents is an unanticipated toxicity associated with biguanides, the defense against which requires post-transcriptional protection of de novo lipogenesis. We demonstrate that biguanide treatment during impaired lipogenesis drives NADPH toxicity, leading to catastrophic elevation of NADH/GSH reducing equivalents and accelerated death across metazoans. Multiple NADPH-generating interventions require de novo lipogenesis to prevent markedly shortened survival, indicating that this defense mechanism is broadly leveraged. We propose that fatty acid biosynthesis is a tunable rheostat which can minimize biguanide-induced reductive stress whilst maximizing its pro-longevity outcomes and serve as an exploitable vulnerability in reductive stress sensitive cancers.2026/05/25GSE277946GSM8535028GSM8535029GSM8535048GSM8535049GSM8535027GSM8535046GSM8535068GSM8535047GSM8535066GSM8535044GSM8535067GSM8535045GSM8535064GSM8535042GSM8535043GSM8535065GSM8535040GSM8535062GSM8535063GSM8535041GSM8535060GSM8535061GSM8535039GSM8535037GSM8535059GSM8535038GSM8535057GSM8535035GSM8535058GSM8535036GSM8535055GSM8535033GSM8535034GSM8535056GSM8535053GSM8535031GSM8535054GSM8535032GSM8535051GSM8535052GSM8535030GSM853505022765277946Caenorhabditis elegans