In the original publication [...].

ABSTRACT Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder characterized by cognitive decline and neuropsychiatric symptoms such as anxiety and depression. Approximately 75% of AD patients suffer from anxiety. Aging is the foremost detrimental factor for AD and anxiety; thus, anxiety disorder brings obstacles to clinical diagnosis and management of AD patients. Although a few FDA-approved drugs available for AD in recent years, these drugs only provide symptomatic relief, cannot slow down or reverse AD progression in the advanced stages, and anxiety associated with AD. There is mounting evidence that gamma-aminobutyric acidergic (GABAergic) system plays a role in the pathogenesis of AD and anxiety. However, how GABAergic system dysfunction results in AD-related anxiety is unknown. In the present review, we aimed to summarize the mechanisms of GABAergic system in AD-related anxiety and provide with theory help for AD-related anxiety therapeutics. We propose a concept of an interactive mechanism framework of GABAergic system in anxiety and AD progression. Regulation of GABAergic system associated with AD can provide a potential intervention for this devastating disease and the comorbidity of anxiety.

Parkinson’s disease (PD) is a common neurodegenerative disease with multiple causes and complex mechanisms. Mitochondrial dysfunction is the main cause and central event of dopaminergic neuron degeneration in PD. Therefore, studying mitochondrial dysfunction plays an important role in understanding the pathogenesis of PD. In the future, mitochondrial dysfunction becomes an important therapeutic target for this disease. This article focuses on the mitochondrial molecular mechanism of neurodegeneration, including reactive oxygen species generation, mitochondrial autophagy, and mitochondrial dynamics, etc., and the potential targets for PD therapy. This article also discusses other potential treatment strategies, such as mitochondrial transplantation, targeted microRNA, use of stem cells and exercise, these may provide valuable insights for clinical practice. A better understanding of the role of mitochondria in the pathophysiology of PD may provide fundamental principles for designing new therapeutic interventions to combat PD.

The formation of lipidated Gamma-Aminobutyric Acid Receptor-Associated Protein (GABARAP), which is a crucial subfamily in the Autophagy-associated protein 8 (Atg8) group, not only requires the intricate collaboration of other autophagy-related proteins, but acts to necessarily promote the conduction of autophagy and Gamma-Aminobutyric Acid (GABA) A Receptor (GABAAR) trafficking. The molecular pathway on the formation of GABARAP is same as LC3-II, in which GABARAP is activated through Autophagy Activating Kinase 1 (ULK-1), Atg12-Atg5-Atg16L1 and Atg 4, whereas Rapamycin Complex 1 (mTORC1) and AMP-activated protein kinase (AMPK) inhibit Ulk1. The lipidated GABARAP interacts with molecules related to the synapse and regulates GABAAR clustering through interactions with postsynaptic scaffolding proteins, such as gephyrin and Ankyrin. GABARAP plays roles in regulating synaptic functions besides autophagy.

AIMS:Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the aggregation of alpha-synuclein (α-syn) in Lewy bodies. Emerging studies find that disruption of the Golgi structure and Golgi stress are involved in PD. Thioredoxin-1 (Trx-1) is a redox regulatory protein that protects DA neurons from methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damage. However, whether Trx-1 can protect DA neurons against MPTP-induced Golgi stress is still unknown. RESULTS:We first made sure that MPTP led to the loss of DA neurons in the SNpc and motor impairment in mice, which was reversed in Trx-1 overexpression mice. Trx-1 overexpression suppressed Golgi apparatus fragmentation, α-syn aggregation, oxidative stress, and protein kinase C zeta expression increased by MPTP. Trx-1 overexpression restored the colocalization of Trx-1 and tyrosine hydroxylase with Golgi matrix protein 130 (GM130), decreased by MPTP. Moreover, Trx-1 overexpression suppressed the increased co-localization of Leucine-rich repeat kinase 2 and Ras-associated binding protein 29 with vacuolar protein sorting-associated protein 52 induced by MPTP. Trx-1 overexpression suppressed the expression changes of ADP-ribosylation factor 4 and heat shock protein 47, and their colocalization with GM130 induced by MPTP. INNOVATION:Our study reveals a novel mechanism, whereby Trx-1 inhibits Golgi stress in DA neuron induced by MPTP. CONCLUSIONS:These results suggest that Trx-1 may regulate the development of PD through inhibiting Golgi stress and is a potential new molecular target and therapeutic strategy for Golgi stress involved in PD. Antioxid. Redox Signal. 44, 661-675.

Despite hyposmia being a dominant non-motor manifestation of Parkinson's disease (PD), its underlying driving mechanisms are poorly defined. The redox protein Thioredoxin-1 (Trx-1) offers neuroprotection against various insults; however, its potential involvement in the neural proliferation in the subventricular zone (SVZ) and neural differentiation in the olfactory bulb (OB) related to MPTP-induced olfactory dysfunction have not been previously established. Our research demonstrates that when Trx-1 is downregulated in the substantia nigra pars compacta (SNpc), MPTP-triggered olfactory deficits are significantly intensified. A key anatomical discovery in our study is the existence of projections from the SNpc to the SVZ. We established that the MPTP-driven death of SNpc dopaminergic (DAergic) neurons correlates with decreased dopamine D1 receptor (D1R) levels in the SVZ, an effect that is magnified by the loss of Trx-1. Alongside D1R reductions, MPTP suppressed a cascade of SVZ signaling molecules (phosphorylated PKA, Wnt3a, β-catenin, Pax6, cyclin D1, and CDK4), with Trx-1 deficiency causing even steeper declines. Furthermore, Trx-1 knockdown hindered the generation of immature neurons and disrupted DAergic neuronal differentiation within the OB. Collectively, our findings suggest that reduced Trx-1 expression in the SNpc may contribute to PD-related olfactory deficits, potentially via inhibiting SVZ neural proliferation, decreasing immature and mature neuron populations, and disrupted differentiation of OB immature neurons. By accelerating MPTP-triggered degeneration of DAergic neurons in the SNpc, Trx-1 downregulation reduces the SVZ of DAergic input. This disruption impairs D1R-mediated the neural proliferation in the SVZ, as well as the maturation and differentiation of immature neurons in OB, ultimately driving the progression of olfactory dysfunction in a PD mouse model.

The clinical utility of morphine is limited by the development of tolerance and addiction. These processes are linked to neuroinflammation involved microglial responses. Thioredoxin-1 (Trx-1) is a crucial endogenous antioxidant with neuroprotective properties, and our previous work has shown that Trx-1 overexpression blocks morphine-induced conditioned place preference (CPP). However, the role of Trx-1 in morphine-induced microglial inflammatory responses remains unclear. Here, we investigated the effects and underlying mechanisms of Trx-1 overexpression on morphine-induced microglial pro-inflammatory shifts, both in the microglial cell line BV-2 and in the ventral tegmental area (VTA) of mice. In vitro, morphine treatment increased intracellular reactive oxygen species (ROS) in BV-2 cells, upregulated markers associated with microglial reactivity (IBA-1 and MHC-II), activated the NF-κB pathway (evidenced by increased p-IκBα and nuclear p65 translocation), and elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) while reducing the anti-inflammatory cytokine IL-10. Overexpression of Trx-1 via adenoviral transduction reversed all these morphine-induced effects. In vivo, using a CPP paradigm, we confirmed that morphine CPP was blocked in Trx-1 transgenic (TG) mice. Biochemical analysis of the VTA from these mice revealed that Trx-1 overexpression similarly attenuated morphine-induced upregulation of IBA-1, MHC-II, and pro-inflammatory cytokines, consistent with in vitro results. Mechanistically, co-immunoprecipitation assays demonstrated an endogenous interaction between Trx-1 and the mu-opioid receptor (MOR). Overexpression of Trx-1 significantly enhanced this interaction and was associated with increased MOR expression. These results reveal that overexpression of Trx-1 suppresses morphine-induced neuroinflammation by binding MOR and reducing ROS-driven NF-κB activation in microglia. This mechanism positions Trx-1 as a potential therapeutic target for improving the clinical safety and efficacy of opioid addiction.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies composed of misfolded alpha-synuclein (α-syn). A growing number of studies indicate that microglia-mediated neuroinflammation and autoimmune responses are important pathological features of PD. Thioredoxin-1 (Trx-1), a multifunctional redox-regulatory protein, exerts neuroprotective effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models, but its impact on microglia-mediated autoimmune responses in PD remains unexplored. In the present study, we demonstrated that Trx-1 suppressed microglial accumulation and the increase of pro-inflammatory cytokines. Furthermore, Trx-1 suppressed the increase of α-syn and major histocompatibility complex class II (MHC-II)-mediated antigen presentation in microglia induced by MPTP. Additionally, MPTP promoted T helper 17 (Th17) cell differentiation, inhibited forkhead box P3 (FOXP3) protein level and regulatory T (Treg) cell differentiation, and enhanced forkhead box O1 (FOXO1) phosphorylation and nuclear exclusion in the SNpc. All these pathological alterations induced by MPTP were effectively restored by Trx-1 overexpression. Our findings highlight the pivotal role of Trx-1 in microglia-mediated autoimmune responses, thereby providing a potential therapeutic target for PD.

Parkinson’s disease (PD) is a neurodegenerative disorder marked by the accumulation of alpha-synuclein protein within dopamine-producing neurons and their consequent death. Although the specific etiology of PD remains unclear, emerging evidences suggest that disrupted neurogenesis plays a crucial role in pathophysiology of PD. Neurogenesis has a regenerative effect and is a promising therapeutic target for PD. Recent studies demonstrated that impaired neurogenesis in the subventricular zone (SVZ), hippocampus (HIP) and substantia nigra (SN) contributed to motor/nonmotor deficits in PD. However, the precise correlation between the pathogenesis of PD and neurogenesis remains to be explored. This study aimed to investigate the role of the dopaminergic signaling pathway, neurotrophic factors, gut microbiota, neuroinflammation, and mutations in PD-related genes in adult neurogenesis in PD. First, a comprehensive review of recent studies was carried out to explore how neurogenesis impacts PD pathophysiology. Then, the challenges and future perspectives associated with promoting endogenous neurogenesis to compensate for the loss of dopaminergic neurons in PD were investigated. The study offers promising therapeutic strategies to activate the endogenous neurogenesis in PD. Furthermore, it offers promising therapeutic strategies to activate the endogenous neurogenesis in PD. This article also emphasizes the importance of the precise manipulation of neurogenesis in PD with the aim of promoting the translation of these findings into clinical treatment.

Alveolar macrophages (AMs) are crucial for lung homeostasis, and their dysfunction causes uncontrolled fibrotic responses and pulmonary disorders. Protein phosphatases control multiple cellular events. However, whether nuclear phosphatases cooperate with histone modifiers to affect pulmonary fibrosis progress remains obscure. Here, we identified pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) as a key protective factor for pulmonary fibrosis. Transcriptomics and epigenomics data confirmed that PHLPP1 selectively targeted Kruppel-like factor 4 (KLF4) for transcriptional inhibition in AMs. Nuclear PHLPP1 directly bound and dephosphorylated histone deacetylase 8 (HDAC8) at serine 39, thereby enhancing its deacetylase enzyme activity and subsequently suppressing KLF4 expression via the decreased histone acetylation and chromatin accessibility. Thus, loss of PHLPP1 amplified KLF4-centric profibrotic transcriptional program in AMs, while intratracheal administration of Klf4-short hairpin RNA (shRNA) adeno-associated virus ameliorated lung fibrosis in PHLPP1-deficient mice. Our study implies that targeting decreased PHLPP1 in AMs might be a promising therapeutic strategy for pulmonary fibrosis.

Methamphetamine (METH) is a widely abused psychoactive drug that readily establishes reward memories contributing to METH relapse. The medial prefrontal cortex (mPFC) is central to cognition, motivation, reward, and emotion, and the hippocampus is critically involved in reward memory. The mPFC possesses an enormous variety of projection neurons. However, the direct projection from the mPFC to the hippocampus involved in METH addiction has not been studied well. To explore the role of a mPFC-hippocampus pathway of regulating METH reward memory, conditioned place preference (CPP) was used to detect reward memory and recombinant adeno-associated virus 2/9s (rAAV2/9s) were used to label neurons, identify projections, and optogenetically explore involvement of the male mice mPFC-hippocampus pathway in regulating METH-CPP. We found that a novel prelimbic prefrontal cortex (PrL) projection directly to the dorsal hippocampus CA1 (dCA1) regulated CPP induced by METH. Moreover, optogenetic activation or inhibition and silencing the PrL to dCA1 glutamatergic pathway with tetanus neurotoxin (TeNT) modulated METH-CPP. Our results reveal a PrL to dCA1 glutamatergic pathway that regulates METH-CPP and could serve as a potential target for treating METH use disorder.

Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide, currently lacks effective treatment options due to its complex pathogenesis. Growing evidence in recent years demonstrates that intracellular Calcium (Ca²⁺) homeostasis disruption plays a critical role in PD development and progression. Ca²⁺ imbalance not only causes Ca²⁺-dependent synaptic dysfunction and impaired neuronal plasticity but also leads to progressive neuronal loss, collectively forming the core pathological characteristics of PD neurodegeneration. Notably, mitochondrial Ca²⁺ imbalance has been identified as a key pathogenic factor in PD. As vital intracellular Ca²⁺ regulators, dysfunctional mitochondria can induce abnormal opening of the mitochondrial permeability transition pore (mPTP), triggering apoptotic cascades. Furthermore, mitochondrial Ca²⁺ overload disrupts oxidative phosphorylation, resulting in excessive reactive oxygen species production that exacerbates neuronal damage. Recent studies reveal the essential role of mitochondria-endoplasmic reticulum interactions in maintaining Ca²⁺ homeostasis, with these organelles forming structurally and functionally integrated connections through mitochondrial ER-associated membrane (MAM) to cooperatively regulate Ca²⁺ ion dynamics. This review describes the molecular mechanisms of mitochondrial Ca²⁺ imbalance in PD pathogenesis and summarizes the potential of mitochondrial channels and MAM-associated proteins as PD therapeutic targets. By thoroughly analyzing these targets mechanisms, we aim to provide a theoretical foundation for developing novel PD treatment strategies based on Ca²⁺ homeostasis regulation. These findings not only expand our understanding of PD pathogenesis but also point toward developing targeted neuroprotective therapies.

Aims: Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuron degeneration in the substantia nigra pars compacta (SNpc). Thioredoxin-1 (Trx-1) is a redox protein that protects neurons from various injuries. Our study revealed that Trx-1 overexpression improved the learning and memory impairments induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the role of the specific transmission of signals from the SNpc to the hippocampus regulated by Trx-1 in cognition deficits associated with PD is still unknown. Results: We observed that Trx-1 downregulation in the SNpc aggravated cognitive dysfunction induced by MPTP. Importantly, we observed that the SNpc directly projects to the hippocampus. We found that the loss of DAergic neurons in the SNpc induced by MPTP resulted in a decrease in dopamine D1 receptor (D1R) expression in the hippocampus, which was promoted by Trx-1 downregulation in the SNpc. The levels of phosphorylated extracellular signal-regulated kinase (p-ERK1/2), phosphorylated cAMP-response element binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95) in the hippocampus were decreased by MPTP and further decreased by Trx-1 downregulation in the SNpc. Finally, the number of synapses in the hippocampus was decreased by MPTP in the hippocampus and further reduced by Trx-1 downregulation in the SNpc. Innovation: Trx-1 downregulation accelerated the loss of DAergic neurons in the SNpc, leading to a decrease in the number dopaminergic projections to the hippocampus, subsequently inhibiting the D1R-ERK1/2-CREB-BDNF pathway in the hippocampus, and ultimately impairing hippocampus-dependent cognition. Conclusions: These results indicate that a decrease in Trx-1 level in the SNpc plays a critical regulatory role in cognitive dysfunction in individuals with PD by decreasing the hippocampal D1R signaling pathway. Antioxid. Redox Signal. 00, 000-000.

Neutrophils play a critical role in the pathogenesis of autoimmune diseases, including myasthenia gravis (MG), but their specific function in MG exacerbations remains unclear. This study utilizes single-cell RNA sequencing (scRNA-seq) of bone marrow and peripheral blood from MG patients during acute exacerbations, combined with experimental autoimmune myasthenia gravis (EAMG) mouse models and clinical cohort analyses, to investigate the potential involvement of a neutrophil-B-cell activating factor (BAFF) -plasma cell axis. The results reveal that, during MG acute exacerbation, bone-marrow neutrophils exhibit significantly enhanced maturation. Upon migration to the peripheral blood, these neutrophils secrete increased amounts of BAFF, further promoting pathological B-cell differentiation and plasma cell activation. Moreover, gene knockout models and serum cytokine analyses reveal that the IFN-γ signaling pathway is a key driver of this excessive BAFF secretion, supporting the existence of a neutrophil-BAFF-plasma cell interaction relevant to MG exacerbation. Clinical data analysis shows that MG patients with high baseline neutrophil levels derive greater benefit from treatment with the BAFF/APRIL dual-target inhibitor telitacicept. Collectively, this study reveals the mechanistic link between neutrophil activation and MG exacerbation, providing insights that may inform precision-targeted immunotherapy.

Research context reveals that major depressive disorder (MDD), as a prevalent chronic relapsing psychiatric condition affecting up to one-third of patients with treatment resistance, necessitates urgent development of novel therapeutic agents. Emerging evidence implicates neuroinflammatory mechanisms in MDD pathophysiology, while the antidepressant potential of Ganoderic acid A (GAA), a triterpenoid compound derived from Ganoderma lucidum, particularly through modulation of lipopolysaccharide (LPS)-induced depression-like behaviors via acute neuroinflammation suppression remains underexplored. This study demonstrates for the first time that GAA administration significantly inhibits cerebral inflammatory activity and exhibits antidepressant properties in LPS-challenged murine models. Experimental protocols involved male C57BL/6 mice receiving intraperitoneal LPS injections (2 mg/kg) to establish depression-like phenotypes, with control and treatment groups administered saline or GAA (2.5 mg/kg) respectively. Behavioral assessments incorporating sucrose preference tests, forced swimming assays, and tail suspension evaluations were conducted. Neurobiological analyses quantified prefrontal cortex (PFC) protein expression of Iba1, iNOS, and GFAP through immunofluorescence techniques, with parallel measurements of caspase-1 and IL-1β levels using comparable methodology. Inflammatory cell infiltration in PFC regions was histologically evaluated via hematoxylin–eosin staining protocols.Key findings demonstrate that GAA intervention not only ameliorated LPS-induced depression-like behavioral manifestations but crucically modulated neuroinflammatory pathways through downregulation of microglial and astrocytic activation states in the PFC. Specific reductions in caspase-1 and IL-1β inflammatory mediators were quantitatively confirmed, substantiating the compound’s mechanism of action through targeted neuroimmune regulation. These results provide experimental validation for GAA’s therapeutic potential as an antidepressant agent operating via neuroinflammation suppression paradigms, offering critical insights for developing novel MDD treatments targeting inflammatory pathomechanisms.

Arsenic in the environment, such as sodium arsenic (NaAsO2), is a frequently occurring hazard that has been linked to nonalcoholic steatohepatitis (NASH). Our prior research established the involvement of ferroptosis in arsenic-induced NASH, but the precise underlying mechanisms remain elusive. Here, we found that exposure to NaAsO2 had a suppressive effect on the expression of CDGSH iron-sulfur domain-containing protein 2 (CISD2) at the protein and gene levels, and overexpression of CISD2 inhibited NaAsO2-induced ferroptosis and NASH. Additionally, administration of NaAsO2 to hepatocytes triggered mitochondrial dysfunction, manifesting as the release of cytochrome c, impairment of the mitochondrial respiratory chain, and reduction in ATP synthesis. However, these adverse effects were alleviated through overexpression of CISD2. Intracellular iron redistribution was induced by overexpression of CISD2 and inhibited NaAsO2-induced ferroptosis. This inhibition was characterized by a reduction in cytoplasmic iron levels and an increase in mitochondrial iron levels. Our study demonstrated that NaAsO2 induced intracellular iron reorganization and mitochondrial dysfunction through CISD2 inhibition, leading to ferroptosis and NASH. This may provide a novel means of treatment of nonalcoholic fatty liver disease triggered by environmental factors.

Background/Objectives: MIDN (midnolin) is newly discovered method for critically regulating a ubiquitin-independent proteasomal degradation pathway. This study aims to examine the expression, prognostic value, genomic changes, interacting proteins, methylation status, and correlations with the tumor immune microenvironment of MIDN in various cancers. Methods: The GTEx, Depmap, GEPIA2, and Kaplan–Meier Plotter databases are applied to evaluate the MIDN level in tumor and normal tissues and the MIDN prognostic value in cancers. The genetic alterations of MIDN in cancers are investigated using the cBioPortal database. The STRING, GeneMANIA, DAVID, and Human Protein Atlas are harnessed to identify and analyze MIDN-interacted proteins. The Sangerbox 3.0 platform (a pan-cancer analysis module) is used to measure the correlations between the MIDN level and the tumor immune microenvironment, stemness, immune cell infiltration, tumor mutational burden, immune checkpoint genes, and RNA modification genes. Immunofluorescence, qRT-PCR, and Western blotting assays were used to evaluate the biological roles of MIDN in breast and gastric cancer cells. Results: MIDN expression was dysregulated in many cancers and associated with prognosis in several cancers, such as esophageal cancer. MIDN was mutated in 1.7% of cancers, and deep deletion was the dominant mutation type. NR4A1, PSMC1, and EGR1 were selected as MIDN-interacted proteins, and these four molecules were co-expressed in pancreatic cancer, liver cancer, urothelial cancer, melanoma, and breast cancer. MIDN expression was significantly correlated with the infiltration of CD8+ T cell, CD4+ T cell, B cell, macrophage, neutrophil, and DC both in prostate adenocarcinoma and liver hepatocellular carcinoma. The MIDN level was correlated with several immune checkpoint genes, such as VEGFA, and RNA modification genes such as YTHDF1, YTHDF2, YTHDF3, and YTHDC1 in cancers. Furthermore, in breast cancer cells, the downregulation of MIDN suppressed the colony formation abilities and lessened cell-cycle-associated and stemness-associated genes; in gastric cancer, the knockdown of MIDN diminished the mRNA levels of Nanog and LDHA. Strikingly, silence of MIDN upregulated FTO protein expression in both breast and gastric cancer cells. Conclusions: Our findings demonstrate the expression, prognostic value, mutation status, interacting proteins, methylation status, and correlations with the tumor immune microenvironment of MIDN. MIDN will be developed as a potential therapeutic target and a prognosis biomarker.

The medial prefrontal cortex (mPFC) serves as a critical hub in addiction pathology across binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation/craving stages. This review provides the roles of the mPFC in different stages of addiction, and a focus on the mPFC neurotransmitter systems, neural circuits, molecules and synaptic adaptations on the regulation of addictive behaviors. Neurotransmitter systems of dopaminergic, glutamatergic, and GABAergic imbalances are related to pathological addiction. Circuits of dynamic dysregulation in the mPFC interaction with the striatum, nucleus accumbens (NAc), ventral tegmental area (VTA), dorsal raphe nucleus (DRN), and amygdala drive stage-specific behaviors, such as the prelimbic cortex (PL)→NAc core promoting cocaine-seeking, the infralimbic cortex (IL)→NAc shell suppressing relapse. Alterations in excitation-inhibition of microcircuits pyramidal neurons, GABAergic interneurons impair top-down regulation. Synaptic plasticity induced by drugs is involved in pathological stage-specific addiction, such as persistent craving and compulsive behaviors. Targeting the mPFC circuits offers promising therapeutic strategies for addiction intervention.

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra and the aggregation of alpha-synuclein (α-syn). The central nervous system (CNS) has previously been considered as an immune-privileged area. However, studies have shown that the immune responses are involved in PD. The major histocompatibility complex (MHC) presents antigens from Antigen-presenting cells（APCs） to T lymphocytes, immune responses will be induced. MHCs are expressed in microglia, astrocytes, and dopaminergic neurons. Single nucleotide polymorphisms in MHC are related to the risk of PD. The aggregated α-syn triggers the expression of MHCs by activating glia cells. CD4+ and CD8+ T lymphocytes responses and microglia activation are detected in brains of PD patients. In addiction immune responses further increase blood-brain barrier (BBB) permeability and T cell infiltration in PD. Thus, MHCs are involved in PD through participating in immune and inflammatory responses.

Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignant tumors, and the mechanisms underlying the anti-ferroptosis of esophageal cancer cells are still largely unclear. This study aims to explore the roles of amplified protein kinase C iota (PKCiota) in the ferroptosis of ESCC cells. Cell viability, colony formation, MDA assay, Western blotting, co-IP, PLA, and RNA-seq technologies are used to reveal the roles and mechanisms underlying the PKCiota-induced resistance of ESCC cells to ferroptosis. We showed here that PKCiota was amplified and overexpressed in ESCC and decreased during RSL3-induced ferroptosis of ESCC cells. PKCiota interacted with GPX4 and the deubiquitinase USP14 and improved the protein stability of GPX4 by suppressing the USP14-mediated autophagy–lysosomal degradation pathway. PKCiota was negatively regulated by miR-145-5p, which decreased in esophageal cancer, and also regulated by USP14 and GPX4 by a positive feedback loop. PKCiota silencing and miR-145-5p overexpression suppressed tumor growth of ESCC cells in vivo, respectively; even a combination of silencing PKCiota and RSL3 treatment showed more vital suppressive roles on tumor growth than silencing PKCiota alone. Both PKCiota silencing and miR-145-5p overexpression sensitized ESCC cells to RSL3-induced ferroptosis. These results unveiled that amplified and overexpressed PKCiota induced the resistance of ESCC cells to ferroptosis by suppressing the USP14-mediated autophagic degradation of GPX4. Patients with PKCiota/USP14/GPX4 pathway activation might be sensitive to GPX4-targeted ferroptosis-based therapy.