Ascl4, also known as Achaete-scute complex-like 4, belongs to the superfamily of basic helix-loop-helix transcriptional regulators involved in cell fate determination [4]. It has been associated with the Wnt/β-catenin signaling cascade, which is crucial in the morphogenesis of skin appendages [4]. Additionally, it may play a role in processes such as ferroptosis, fatty acid metabolism, and mitochondrial membrane lipid regulation [1,2,3].

In terms of in vivo studies, Ascl4 null mice showed no overt phenotype, indicating that Ascl4 is non-essential for hair follicle, tooth, or mammary gland development. This suggests that other transcription factors might functionally compensate for its absence [4]. In a context related to ferroptosis, which is a type of programmed cell death, lncRNA TUG1 carried by human urine-derived stem cell-derived exosomes regulated Ascl4-mediated ferroptosis by interacting with SRSF1, protecting against renal ischemia/reperfusion injury [1]. In KRAS-mutated pancreatic cancer, TMOD3 promoted autophagy-dependent degradation of Ascl4, accelerating resistance to immunotherapy [5]. Also, in acute kidney injury, leonurine alleviated the injury by inhibiting ER stress-associated ferroptosis via regulating the ATF4/CHOP/Ascl4 pathway [6].

In conclusion, Ascl4 has a complex role in biological processes. Its dispensability in skin appendage development as shown in Ascl4 null mice provides insights into the redundancy in developmental regulatory networks. In diseases like renal ischemia/reperfusion injury, acute kidney injury, and KRAS-mutated pancreatic cancer, understanding the function of Ascl4 through these in vivo models can potentially lead to the development of new therapeutic strategies targeting related pathways.