Why should cardiac developmental biologist get interested in glycerol phospholipid biosynthesis? 
The answer could be found in the recent paper by Zhao and colleagues (Zhao et al., GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development. Nat Commun. 2025 16(1):3345).

In their work, the authors study the role of Glycerol-3 phosphate acyltransferase 4 (GPAT4) and show its role not merely as a metabolic enzyme but as a player of endocardial integrity and, consequently, of cardiac morphogenesis. By exploiting both global and endocardial‐specific Gpat4 knockout models, the Authors show that loss of GPAT4 triggers an ER stress response selectively in endocardial cells, resulting in augmented ER-mitochondrial communications, mitochondrial dysfunction and endothelial-specific activation of cGAs-STING pathway, a crucial component of the innate immune system. The net result is impaired endocardial survival, aberrant myocardial compaction, and malformations in chamber architecture.

A key strength of the work lies in its mechanistic clarity. GPAT4 is involved in classical pathways of glycerophospholipid biosynthesis, which might have suggested a lipid centric phenotype. Instead, GPAT4 emerges as a guardian of ER homeostasis. This selective buffering of ER stress prevents excessive ER–mitochondrial calcium transfer, thereby preventing mitochondrial calcium overload and the escape of mtDNA into the cytosol. By connecting these intracellular events to heart development, the study fills a substantial gap in our understanding of how organellar crosstalk shapes morphogenesis. Endocardial–myocardial signaling has long been recognized as essential for trabeculation, compaction, and coronary vessel formation, but the upstream regulators of endocardial health have been elusive. GPAT4 now takes its place alongside well recognized pathways as Notch, BMP, and Neuregulin, as a critical node, although operating through organelle biology rather than classical growth factor signaling. The demonstration that genetic ablation of cGAS or STING rescues the lethal cardiac phenotypes of Gpat4 deletion mice is particularly compelling. It not only confirms the pathological role of aberrant mtDNA driven inflammation in the developing heart but also raises the intriguing perspective of modulating innate‐immune sensors to correct congenital defects.

In sum, these findings elevate GPAT4 from a “housekeeping” enzyme to a developmental rheostat that tunes organelle stress and immune signaling to sculpt the heart. This study shed new light on the organellar foundations of cardiac form and function.