Autophagy as a targeted therapeutic approach for skin cancer:Evaluating natural and synthetic molecular interventions

Skin cancer,a prevalent malignancy worldwide,poses significant health concerns owing to its increasing incidence.Autophagy,a natural cellular process,is a pivotal event in skin cancer and has advantageous and detrimental effects.This duality has prompted extensive investigations into medical interventions targeting autophagy modulation for their substantial therapeutic potential.This systematic review aimed to investigate the relationship between skin cancer and autophagy and the contribution and mechanism of autophagy modulators in skin cancer.We outlined the effectiveness and safety of targeting autophagy as a promising therapeutic strategy for the treatment of skin cancer.This comprehensive review identified a diverse array of autophagy modulators with promising potential for the treatment of skin cancer.Each of these compounds demonstrates efficacy through distinct physiological mechanisms that have been elucidated in detail.Interestingly,findings from a literature search indicated that none of the natural,synthetic,or semisynthetic compounds exhibited notable adverse effects in either human or animal models.Consequently,this review offers novel mechanistic and therapeutic perspectives on the targeted modulation of autophagy in skin cancer.

Reductive damage induced autophagy inhibition for tumor therapy

Numerous therapeutic anti-tumor strategies have been developed in recent decades.However,their therapeutic efficacy is reduced by the intrinsic protective autophagy of tumors.Autophagy plays a key role in tumorigenesis and tumor treatment,in which the overproduction of reactive oxygen species(ROS)is recognized as the direct cause of protective autophagy.Only a few molecules have been employed as autophagy inhibitors in tumor therapy to reduce protective autophagy.Among them,hydroxychloroquine is the most commonly used autophagy inhibitor in clinics,but it is severely limited by its high therapeutic dose,significant toxicity,poor reversal efficacy,and nonspecific action.Herein,we demonstrate a reductive-damage strategy to enable tumor therapy by the inhibition of protective autophagy via the catalytic scavenging of ROS using porous nanorods of ceria(PN-CeO_(2))nanozymes as autophagy inhibitor.The antineoplastic effects of PN-CeO_(2)were mediated by its high reductive activity for intratumoral ROS degradation,thereby inhibiting protective autophagy and activating apoptosis by suppressing the activities of phosphatidylinositide 3-kinase/protein kinase B and p38 mitogen-activated protein kinase pathways in human cutaneous squamous cell carcinoma.Further investigation highlighted PN-CeO_(2)as a safe and efficient anti-tumor autophagy inhibitor.Overall,this study presents a reductive-damage strategy as a promising anti-tumor approach that catalytically inhibits autophagy and activates the intrinsic antioxidant pathways of tumor cells and also shows its potential for the therapy of other autophagy-related diseases.

Pharmacological insights into autophagy modulation in autoimmune diseases

As a cellular bulk degradation and survival mechanism,autophagy is implicated in diverse biological processes.Genome-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibility of autoimmune diseases including systemic lupus erythematosus(SLE)and inflammatory bowel disease(IBD),indicating that autophagy dysregulation may be involved in the development of autoimmune diseases.A series of autophagy modulators have displayed protective effects on autoimmune disease models,highlighting the emerging role of autophagy modulators in treating autoimmune diseases.This review explores the roles of autophagy in the autoimmune diseases,with emphasis on four major autoimmune diseases[SLE,rheumatoid arthritis(RA),IBD,and experimental autoimmune encephalomyelitis(EAE)].More importantly,the therapeutic potentials of small molecular autophagy modulators(including autophagy inducers and inhibitors)on autoimmune diseases are comprehensively analyzed.