Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress

Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.

Autophagy is a fundamental eukaryotic pathway that has multiple effects on immunity. Autophagy is induced by pattern recognition receptors and, through autophagic adaptors, it provides a mechanism for the elimination of intracellular microorganisms. Autophagy controls inflammation through regulatory interactions with innate immune signalling pathways, by removing endogenous inflammasome agonists and through effects on the secretion of immune mediators. Moreover, autophagy contributes to antigen presentation and to T cell homeostasis, and it affects T cell repertoires and polarization. Thus, as we discuss in this Review, autophagy has multitiered immunological functions that influence infection, inflammation and immunity.