Histone lactylation mediates maternal cadmium exposure-induced liver fibrosis in male offspring

The liver served as a primary target organ for cadmium (Cd)-induced toxicity. Maternal Cd exposure during gestation and lactation heightened susceptibility to hepatic injury in male offspring, although the underlying mechanisms remained incompletely understood. Through integrated approaches utilizing rat models and in vitro hepatic stellate cells (HSCs) analyses, we demonstrated that maternal Cd exposure induced persistent lactate accumulation and hepatic fibrosis in male offspring. Mechanistically, Cd directly bound to lactate dehydrogenase A (LDHA), enhancing its enzymatic activity without altering protein expression and consequently promoting lactate production. The accumulated lactate specifically drove lactylation at lysine 18 of histone H3 (H3K18la), an epigenetic modification that increases phosphodiesterase 8 A (PDE8A) transcription. This activation suppressed the cAMP/CREB signaling pathway and ultimately triggered HSCs activation. Our findings identify the Lactate→H3K18la→PDE8A→cAMP/CREB cascade as a novel metabolome-epigenome signaling pathway driving persistent liver injury in male offspring following maternal Cd exposure.