Endoplasmic reticulum autophagy in inflammatory diseases

Implication of Proteostasis Impairment and Endoplasmic Reticulum Stress in Age-Related Neurodegeneration

In insights on the research regarding therapeutic approaches of NDs which intend to target molecular components, a general understanding of proteostasis, ER stress, UPR signalling and how these cellular processes are related to neurodegeneration is provided.

Endoplasmic Reticulum Stress-Driven Inflammatory Mediators in Metabolic Disorders: From Molecular Mechanisms to Targeted Therapies.

Nutrient overload induces a state of chronic, low-grade inflammation termed metaflammation, which contributes to the development of metabolic disorders, such as type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). As a nutrient-sensitive organelle, the endoplasmic reticulum (ER) is highly vulnerable to systemic metabolic burden. When its adaptive capacity is exceeded, ER stress (ERS) activates the unfolded protein response (UPR) and drives cellular dysfunction. This review delineates how the canonical UPR sensors transduce metabolic stress into pro-inflammatory signaling cascades. By engaging key transcriptional regulators and inflammasome complexes, these pathways drive the production of inflammatory mediators, including cytokines, chemokines, and bioactive lipids, such as leukotrienes (LTs) and prostaglandins. Subsequently, the review discusses the organ-specific consequences of ERS in the liver, pancreas, adipose tissue, vascular endothelium, and hypothalamus, highlighting how this stress sustains a self-reinforcing cycle of tissue injury and metabolic dysfunction. Emerging therapeutic strategies are also summarized, ranging from broad-spectrum chemical chaperones to precision UPR modulators and organ-targeted delivery systems aimed at disrupting this pathogenic axis and restoring metabolic homeostasis.

Mechanistic insights into lysosomal stress response network in carcinogenesis and therapeutic opportunities.

Lysosomes are vital organelles that maintain cellular homeostasis and orchestrate dynamic adaptations during physiological and pathological stress. Lysosomal damage, caused by various extrinsic and intrinsic factors, impairs its integrity and simultaneously disrupts the normal functioning of other organelles, including the endoplasmic reticulum and mitochondria. Lysosomal homeostasis through the lysosomal stress response (LSR) network aids cells in adapting to organelle damage, nutrient fluctuations, oxidative stress, and metabolic irregularities. This coordinated network is primarily governed by proteins, including mTOR, TFEB/TFE3, AMPK, Rag GTPases, Ragulator, and TRPML1, which integrates mechanisms involving rapid lysosomal membrane repair, selective elimination of extensively damaged lysosomes, de novo lysosomal biogenesis, and lysosomal reformation pathways. Dysregulation of the LSR network leads to different types of diseases, including cancer. This review summarizes the current understanding of lysosomal damage mitigation, particularly in cancer, where remodeling of the LSR network not only enables cancer cells to maintain metabolic plasticity by resisting therapeutic stress and promoting malignancy but also identifies the LSR network as a critical determinant in tumorigenesis. We further provide a detailed discussion of emerging evidence on the disruption of lysosomal homeostasis, highlighting strong links between lysosome-targeting drugs and cancer therapeutics. Altogether, we establish the LSR network as a central regulator of cellular homeostasis, thereby emerging as a promising therapeutic target in cancer and other lysosome-associated disorders.

Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.

Canonical and noncanonical autophagy in immunity

Summary Canonical and noncanonical autophagic processes are integrated with innate and adaptive immunity and sterile or pathogen-induced inflammation. In canonical autophagy, double membrane autophagosomes modified by ubiquitin-like ATG8 proteins in a process termed membrane atg8ylation sequester and eliminate intracellular targets such as invading microbes, defunct organelles, aggregates, and inflammatory molecules. Recently, a plethora of noncanonical processes that entail membrane atg8ylation of various intracellular organelles other than autophagosomes have been linked to immunity. This has led to confounding interpretations and conflation of diverse processes as autophagy. Here, we posit that these are divergent manifestations of a common ancestral homeostatic process of membrane atg8ylation and provide an overview of how they affect immunity and inflammation. These relationships are evident in model organisms and are reflected in human genetic predispositions to diseases with immune components. The membrane atg8ylation pathways affect acute and chronic inflammation, infections, autoimmunity, cancer, neurodegeneration, metabolic syndrome, diabetes, and other disorders.

Macrophage autophagy in allergic diseases: Regulatory mechanisms, immune crosstalk, and therapeutic implications.

Macrophages are pivotal effector cells within the innate immune system, playing a central role in inflammation regulation, tissue homeostasis, and immune defense. Recent studies have demonstrated that macrophage autophagy-a highly conserved process essential for cellular homeostasis-plays a critical role in dynamically balancing immune responses by selectively eliminating damaged organelles, pathogens, and protein aggregates. Macrophage autophagy is finely regulated by various signaling pathways, such as mTOR and NF-κB, and its dysfunction is closely associated with the onset and progression of allergic diseases. This review systematically synthesizes the molecular mechanisms governing macrophage autophagy and its dual role in allergic diseases, including allergic rhinitis, asthma, and atopic dermatitis. It highlights the functions of key signaling pathways (e.g., mTOR, NF-κB) and regulatory factors (e.g., p62, Beclin-1, LC3) and explores the crosstalk between macrophage autophagy, immunometabolism, and cellular polarization. Explores the crosstalk between macrophage autophagy, immunometabolism, and cellular polarization, and further elaborates the reciprocal regulatory network of autophagy and metabolic reprogramming within allergic inflammatory microenvironment. Furthermore, the review summarizes potential therapeutic strategies targeting macrophage autophagy, such as budesonide/simvastatin combination therapy and rapamycin derivatives, along with their clinical translation prospects, with the aim of providing a theoretical foundation for developing novel, autophagy-targeted precision therapies for allergic diseases.