Paneth cells as orchestrators of epithelial barrier defense and emerging therapeutic targets in inflammatory bowel disease.

First described by Joseph Paneth in 1888 in the small intestine, particularly in the crypts of Lieberkühn, Paneth cells have since emerged as a critical subtype of intestinal epithelial cells (IECs), which together constitute the body’s largest interface with the external environment, continuously exposed to pathogens, dietary components, and toxins. Paneth cells represent a unique, long-lived secretory IEC population located at the crypt base, where they play indispensable roles in antimicrobial defense and stem cell niche maintenance. Their differentiation, positioning, and survival are governed by tightly regulated signaling networks, including the Wnt and Notch pathway. Although traditionally viewed as terminally differentiated, emerging evidence suggests Paneth cells possess a certain level of plasticity, enabling functional adaptation or dedifferentiation under stress or injury. These characteristics position Paneth cells as central regulators of intestinal homeostasis and epithelial barrier integrity. Over the last decades, accumulating evidence has established that Paneth cell dysfunction is closely linked to microbial dysbiosis and the development of inflammatory bowel disease (IBD), highlighting their contribution to disease pathogenesis. Recent discoveries on how Paneth cell dysfunction contributes to intestinal inflammation are uncovering new therapeutic approaches aimed at reestablishing Paneth cell homeostasis and alleviating IBD progression. In this review, we comprehensively summarize current knowledge on Paneth cell differentiation, function, and their role in gut host defense and epithelial barrier maintenance. We further discuss mechanisms by which Paneth cell dysfunction disrupts intestinal homeostasis, promoting IBD development, and highlight emerging therapeutic strategies that target Paneth cells to reestablish barrier integrity and restore gut health.