# X‐Box binding protein 1 downregulates SIRT6 to promote injury in pancreatic ductal epithelial cells

## TL;DR

This study shows that XBP1 reduces SIRT6 levels in pancreatic cells, leading to cell damage and suggesting new treatment targets for acute pancreatitis.

## Contribution

The novel finding is that XBP1 downregulates SIRT6, contributing to cellular injury in acute pancreatitis.

## Key findings

- Caerulein treatment decreases SIRT6 and increases XBP1 in HPDE cells.
- XBP1 negatively regulates SIRT6, reversing its protective effects on cells.
- Inhibiting XBP1 or increasing SIRT6 may help treat acute pancreatitis.

## Abstract

Acute pancreatitis (AP) stands as a frequent cause for clinical emergency hospital admissions. The X‐box binding protein 1 (XBP1) was found to be implicated in pancreatic acinar cell apoptosis. The objective is to unveil the potential mechanisms governed by XBP1 and SIRT6 in the context of AP.

Caerulein‐treated human pancreatic duct epithelial (HPDE) cells to establish an in vitro research model. The levels and regulatory role of SIRT6 in the treated cells were evaluated, including its effects on inflammatory responses, oxidative stress, apoptosis, and endoplasmic reticulum stress. The relationship between XBP1 and SIRT6 was explored by luciferase and ChIP experiments. Furthermore, the effect of XBP1 overexpression on the regulatory function of SIRT6 on cells was evaluated.

Caerulein promoted the decrease of SIRT6 and the increase of XBP1 in HPDE cells. Overexpression of SIRT6 slowed down the secretion of inflammatory factors, oxidative stress, apoptosis level, and endoplasmic reticulum stress in HPDE cells. However, XBP1 negatively regulated SIRT6, and XBP1 overexpression partially reversed the regulation of SIRT6 on the above aspects.

Our study illuminates the role of XBP1 in downregulating SIRT6 in HPDE cells, thereby promoting cellular injury. Inhibiting XBP1 or augmenting SIRT6 levels holds promise in preserving cell function and represents a potential therapeutic avenue in the management of AP.

Based on JASPAR, XBP1 is thought to bind to the SIRT6 promoter for regulation. XBP1 levels were found to be significantly upregulated under caerulein treatment and negatively regulate SIRT6.