p4htm acts as a non-redundant regulator of HIF signaling to govern erythropoiesis and renal homeostasis in zebrafish

The cellular response to hypoxia is primarily orchestrated by the HIF (hypoxia-inducible factor) pathway, whose stability is regulated by PHD (prolyl hydroxylase domain) proteins. While PHD2 (prolyl hydroxylase domain-containing protein 2) serves as the principal regulator of HIF-α (hypoxia-inducible factor-α) stability and PHD1/3 (prolyl hydroxylase domain-containing protein 1/3) play subsidiary roles, the physiological function of P4HTM (prolyl 4-hydroxylase, transmembrane) remains poorly defined. Here, we demonstrate that p4htm knockout zebrafish exhibit constitutive Hif activation and develop systemic pathologies including erythrocytosis, pathological cardiac remodeling, and a novel HIF-dependent hepatic steatosis. Importantly, we establish that both pericardial edema and renal defects in p4htm mutants are mechanistically dependent on Hif signaling, as evidenced by rescue with Hif-α inhibition. Our findings identify p4htm as a key physiological regulator of Hif-mediated homeostasis in cardiovascular, renal, and metabolic systems.