IXA4 is a highly selective, non-toxic IRE1/XBP1s activator that induces endoplasmic reticulum (ER) proteostasis remodeling[1]. IXA4 activates IRE1/XBP1 signaling but does not fully activate the unfolded protein response (UPR) or other stress response signaling pathways[2]. IXA4 reduces the secretion of amyloid precursor protein (APP) through IRE1 activation and prevents APP-related mitochondrial dysfunction[3].
In vitro, IXA4 (30μM) treatment of mouse splenic T cells for 4 days significantly increased mitochondrial mass and mitochondrial ATP reserves in cells[4]. IXA4 (10μM) treatment of CHO7PA2 cells expressing the V717F APP (APPV717F) mutant for 18h reduced the level of β-amyloid protein (Aβ) by 50%[5].
In vivo, IXA4 (50mg/kg) was treated with diet-induced obese (DIO) mice by intraperitoneal injection for 8 weeks, which selectively activated IRE1/XBP1s signaling in the liver of mice, improved glucose homeostasis, inhibited hepatic gluconeogenesis, and reduced the expression of key lipogenic genes in the liver (including Dgat2, Scd1, and Srebf1c)[6].
References:
[1] Siwecka N, Rozpędek-Kamińska W, Wawrzynkiewicz A, et al. The structure, activation and signaling of IRE1 and its role in determining cell fate[J]. Biomedicines, 2021, 9(2): 156.
[2] Wang H, Karnati S, Madhusudhan T. Regulation of the homeostatic unfolded protein response in diabetic nephropathy[J]. Pharmaceuticals, 2022, 15(4): 401.
[3] Cummins N, Taylor R C. A stress-free stress response[J]. Nature Chemical Biology, 2020, 16(10): 1038-1039.
[4] Riesenberg B P, Gandy E J, Kennedy A S, et al. Adaptive IRE1 Signaling Elicits T Cell Metabolic Remodeling and Tumor Control[J]. bioRxiv, 2023: 2023.11. 16.567431.
[5] Grandjean J M D, Madhavan A, Cech L, et al. Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming[J]. Nature chemical biology, 2020, 16(10): 1052-1061.
[6] Madhavan A, Kok B P, Rius B, et al. Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity[J]. Nature communications, 2022, 13(1): 608.