Reticulon-3 in endoplasmic reticulum remodeling and cardiometabolic-fibrotic disease

Reticulon-3 (RTN3) was initially studied as an endoplasmic reticulum (ER)-resident reticulon family protein involved in membrane shaping, apoptosis, and amyloid precursor protein processing. More recent work has considerably expanded this view and now places RTN3 at the intersection of ER remodeling, selective ER-phagy, cargo trafficking, lipid handling, and stress signaling. This shift is especially relevant to pharmacology, because RTN3 appears to exhibit heterogeneous effects across tissues and disease states: RTN3 upregulation is maladaptive in obesity, nonalcoholic fatty liver disease, cardiac lipotoxicity, post-myocardial infarction heart failure, and some vascular conditions, whereas RTN3 loss aggravates renal injury, renal fibrosis, and pulmonary fibrosis. Viral infection and hepatocellular carcinoma further illustrate that RTN3 can either support membrane remodeling programs or constrain disease progression, depending on the biological environment. In this review, we reorganize RTN3 biology around mechanism-driven processes and discuss how these processes converge on cardiometabolic, fibrotic, infectious, and oncologic phenotypes. Current evidence suggests that RTN3 is better regarded as a membrane organizing regulator with therapeutic potential rather than a disease specific marker. However, future efforts to target RTN3 will likely need to consider tissue type and pathway specificity.