Daily Endocrinology Research Analysis

Within each cell, metabolite-sensing factors respond to coordinate metabolic homeostasis. How metabolic homeostasis is regulated intercellularly and how this may become dysregulated with age, however, remains underexplored. Here we describe a system regulated by a metabolite sensor, CtBP2. CtBP2 is secreted via exosomes in response to reductive metabolism, which is suppressed by oxidative stress. Exosomal CtBP2 administration extends lifespan in aged mice and improves healthspan in particular by reducing frailty. Mechanistically, we identify activation of CYB5R3 and AMPK downstream of exosomal CtBP2. Consistently, serum CtBP2 levels decrease with age and are negatively associated with cardiovascular disease incidence in humans yet are elevated in individuals from families with a history of longevity. Together our findings define a CtBP2-mediated metabolic system with potential for future clinical applications.

IMPORTANCE: Thyroid eye disease (TED), a disfiguring and potentially sight-threatening condition with racial phenotypic variations, currently has limited effective treatments. Insulin-like growth factor 1 receptor (IGF-1R) inhibitors therapy has emerged as a promising treatment option, although it remains less accessible and lacks substantial evidence in Asian patients. OBJECTIVE: To assess efficacy and safety of IBI311, an IGF-1R inhibitor with an identical amino acid sequence to teprotumumab but a different dosage form, in Chinese patients with active TED. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, double-masked, placebo-controlled, multicenter, 24-week phase 3 trial with recruitment conducted across 20 tertiary hospitals in China from May to December 2023. Chinese participants with active (clinical activity score [CAS] ≥3) moderate to severe TED were included after excluding individuals with active TED onset over 270 days; sight-threatening TED; or history of steroid pulse therapy, radiotherapy, or surgery for TED. INTERVENTIONS: Eighty-two participants were randomized 2:1 to receive intravenous infusions of either IBI311 or placebo once every 3 weeks for 21 weeks with follow-up through week 24. MAIN OUTCOMES AND MEASURES: The primary outcome was the proptosis response rate (proptosis reduction ≥2 mm) in the study eye at week 24.

Atherosclerosis persists as a principal driver of global cardiovascular mortality and morbidity, and its sustained prevalence surge fuels the incidence of major adverse cardiovascular events (MACE). Plaque instability is a critical determinant of MACE, as fissure formation or rupture of vulnerable plaques can precipitate thromboembolic complications. In this study, we investigate a noncanonical role of proprotein convertase subtilisin/kexin type 9 (PCSK9) beyond its lipid regulatory function, focusing on its impact on vascular smooth muscle cells (VSMCs) in the context of plaque instability. Our results demonstrate that PCSK9 overactivity markedly promotes ferroptotic cell death in VSMCs, thereby exacerbating plaque vulnerability. Furthermore, we delineate the underlying mechanism: PCSK9 physically interacts with Yes-associated protein 1 and targets it for lysosomal degradation, which, in turn, suppresses the expression of nuclear protein 1. In conclusion, our findings unveil a novel role of PCSK9 in promoting plaque instability by driving ferroptosis in VSMCs, suggesting that targeting PCSK9 presents a potential avenue for plaque stabilization, thereby mitigating the incidence of major MACE.