Intraperitoneal inflammation is the most important determinant of peritoneal fibrosis in patients with long-term peritoneal dialysis (PD). Spliced x-box binding protein-1 (XBP1s), a major proximal effector of unfolded protein response (UPR) signaling, plays an indispensable role in inflammation. Our study demonstrated that the inflammatory factor interleukin-1β (IL-1β) dose-and time-dependently induced XBP1s upregulation and interleukin-6 (IL-6) secretion, as well as the expression of the fibrotic marker fibronectin. However, these effects were prevented by the IRE1 endonuclease inhibitor STF083010 since it time-dependently reduced IL-1β-induced Xbp1 mRNA splicing, XBP1s protein expression, inflammatory factor IL-6 secretion and the expression of the fibrotic marker fibronectin in human peritoneal mesothelial cells (HPMCs). The overexpression and knockdown of XBP1s in HPMCs had a similar effect on fibronectin expression. In a rat model of peritoneal inflammation, STF083010 significantly attenuated chlorhexidine digluconate-induced XBP1s and α-smooth muscle actin expression, as well as fibrotic tissue proliferation, in the peritoneum. Our results suggest that XBP1s is a strong pathogenic factor that mediates inflammation-induced peritoneal fibrosis in peritoneal dialysis.Peritoneal dialysis (PD) is one of the major effective forms of renal replacement for the treatment of end stage renal diseases (ESRD) 1 , especially within the first five years of dialysis. The population of patients undergoing PD has recently begun to increase sharply throughout the world, particularly in developing countries such as China, due to the implementation of improved healthcare policies 2 . However, the advantages of PD gradually weaken after the first five years of dialysis because of chronic peritoneal dysfunction, which is characterized by inflammation, peritoneal fibrosis and neo-angiogenesis at the lesion site 3 .Several factors contribute to peritoneal inflammation during long-term PD. These factors include (1) the inflammatory status of chronic kidney disease as a result of a reduction in the renal clearance of cytokines, fluid overload, immunological dysfunction and infectious comorbidity 4 , (2) long-term exposure of the peritoneal membrane to unphysiological dialytic solutions with high glucose and low pH 5 , (3) PD-related peritonitis 6 , (4) uremia-induced inflammation in the peritoneum 7 , and (5) protein energy wasting 8 . These factors are usually related to one other and eventually lead to peritoneal fibrosis. Therefore, intraperitoneal inflammation-induced peritoneal fibrosis is the greatest challenge for long-term PD therapy thus far.Inositol-requiring enzyme-1α (IRE1α)/X-box-binding protein 1 (XBP1) signaling is the most important pathway for the unfolded protein response (UPR)/endoplasmic reticulum (ER) stress. It has been revealed that, upon ER stress, unconventional splicing of Xbp1 mRNA occurs to generate spliced Xbp1 (Xbp1s) 9 . Xbp1s encodes an active transcription factor, XBP1s, which drives the expression of...