Insights into the regulation and signaling landscape of cardiotrophin-like cytokine factor 1 (CLCF1).

Cardiotrophin-like cytokine factor 1 (CLCF1) is an essential gene that shows exceptional sequence conservation among vertebrates. CLCF1 loss-of-function mutations cause Crisponi/cold-induced sweating syndrome-2, a disorder with severe and complex phenotypes, underscoring the non-redundant roles of CLCF1. Initially identified as a member of the interleukin-6 (IL-6) cytokine family with activity in neurons and immune cells, CLCF1 is now recognized for broader roles in thermoregulation, glomerular function, myelopoiesis, oncogenesis, and muscle fitness. Despite growing interest in the multifaceted biology of CLCF1, the mechanisms regulating its transcription, translation, secretion, receptor binding, and signaling remain incompletely understood. This review integrates data from multiple open databases and functional studies to outline the current state of knowledge regarding CLCF1 regulatory landscape, receptor interactions, and downstream signaling. It also highlights recent discoveries about the CLCF1 interactome and intracellular functions and underlines its emerging potential as a therapeutic target.