Farmakologiczna modulacja IRE1 w nowotworach i chorobach neurodegeneracyjnych: perspektywy terapeutyczne

The endoplasmic reticulum (ER) plays a key role in protein synthesis, folding and transport. Under pathological conditions, such as those caused by cancer and neurodegenerative diseases, misfolded proteins accumulate, compromising the ER’s ability to maintain cellular homeostasis. Resulting in a toxic condition, called endoplasmic reticulum stress (ER stress), it leads to the activation of a cellular signaling pathway - the Unfolded Protein Response (UPR). As a key sensor of the UPR, the Inositol-requiring enzyme 1 (IRE1α) protein regulates adaptation to new conditions or, in the case of irreversible ER stress, cell apoptosis.Analysis of scientific literature highlights IRE1’s multifaceted activity as a compelling therapeutic target, especially for tackling drug-resistant cancers or neurodegenerative disorders. The presence of two domains in the structure of IRE1 allows the design of a variety of molecules that could target different stages of UPR signaling. However, despite the existence of IRE1 inhibitors, their specificity lacks precision, while the presence of numerous side effects limits their clinical applicability. The complexity of this topic makes the search for new modulators a significant challenge.This review aims to explore the role of IRE1 in regulating ER stress and its impact on the development of chronic diseases. Moreover, it presents recent advances in the pharmacological modulation of IRE1, emphasizing the potential of this pathway to modify the UPR response. Special attention is given to the necessity for continued research into developing new compounds with greater specificity and reduced toxicity profiles, paving the way for potential clinical applications in treating ER stress-related conditions. A literature review was conducted using PubMed and Google Scholar, focusing on the most recent scientific data.