Deciphering the mechanistic involvement of PANoptosis in FC-MDD comorbidity through the gut-brain axis

Functional constipation (FC) is closely associated with major depressive disorder (MDD). Patients suffering from chronic constipation often develop psychological issues such as anxiety and low mood due to persistent physical discomfort. These emotional disturbances can become prolonged, ultimately progressing into depression. Patients with major depressive disorder frequently experience gastrointestinal dysfunction, including diarrhea and constipation, with constipation symptoms being particularly persistent. The co-occurrence of these conditions is extremely common in clinical practice and severely compromises patients' physical and mental health. PANoptosis represents a pan-inflammatory form of programmed cell death (PCD). Unlike single-pathway PCD, it simultaneously engages pyroptosis, apoptosis, and necrosis within a single cell by recruiting key molecules from multiple PCD pathways, accompanied by massive inflammatory cytokine release. This review analyzes the panoptosis mechanism in FC-MDD based on bidirectional regulation of the gut-brain axis, offering a novel perspective on elucidating its comorbidity pathology. However, current evidence primarily stems from animal models and mechanistic studies, with limited direct clinical data on FC-MDD. Future efforts should validate these findings in clinical populations, explore the specific roles of PANoptosome complex subtypes, develop targeted intervention strategies, and advance basic research toward clinical translation to identify more precise therapeutic targets for FC-MDD.