FoxO signaling in regulated cell death and its therapeutic implications in inflammation

Inflammation drives the pathogenesis of diverse inflammatory diseases, posing a profound global health burden. Regulated cell death (RCD) has emerged as a critical mediator of inflammatory outcome and contribute to whether inflammation resolves or progresses to irreversible tissue injury. Forkhead box O (FoxO) transcription factors function as essential integration hub for the sensing of inflammatory signals and the ultimate decision-making power regarding cell fates. This review critically deconstructs the FoxO signaling network in tissues and its regulatory modulation in the inflammatory milieu. We established a robust regulatory framework that encompasses the dual roles of FoxO isoforms across the full spectrum of RCD modalities, ranging from apoptosis and autophagy-dependent cell death (ADCD) to necroptosis, pyroptosis, ferroptosis, cuproptosis, and immunogenic cell death (ICD) during inflammation. Crucially, we highlight the functional dichotomy of FoxOs, revealing their capacity to either facilitate resolution or exacerbate inflammatory injury through RCD regulation. In addition, we evaluated emerging therapeutic approaches targeting the FoxO-RCD axis, including nucleocytoplasmic shuttling modulation and PROTACs. Therapeutic interventions are proposed to distinguish their features from those of other therapies for inflammatory diseases. Overall, this work establishes a novel theoretical framework for the "FoxO-RCD-Inflammation" axis. Our work elucidates the molecular mechanisms involved and thus provides a foundation and prospective precision therapeutics for restoring tissue homeostasis in inflammatory diseases.