Aging phenotype in AD brain organoids: Track to success and challenges.

Alzheimer's disease (AD) poses a complex challenge, with abnormal protein accumulation in the brain causing memory loss and cognitive decline. Traditional models fall short in AD research, prompting interest in 3D brain organoids (BOs) from human stem cells. These findings hold promise for unveiling the mechanisms of AD, especially in relation to aging. However, an understanding of the aging impact of AD remains elusive. BOs offer insight but face challenges. This review delves into the role of BOs in deciphering aging-related AD and acknowledges limitations. Strategies to enhance BOs for accurate aging modeling in AD brains are suggested. Strengthened by molecular advancements, BOs have the potential to uncover the aging phenotype, advancing AD research.

Ototoxicity of polystyrene nanoplastics in mice, HEI-OC1 cells and zebrafish.

Polystyrene nanoplastics are a novel class of pollutants. They are easily absorbed by living organisms, and their potential toxicity has raised concerns. However, the impact of polystyrene nanoplastics on auditory organs remains unknown. Here, our results showed that polystyrene nanoplastics entered the cochlea of mice, HEI-OC1 cells, and lateral line hair cells of zebrafish, causing cellular injury and increasing apoptosis. Additionally, we found that exposure to polystyrene nanoplastics resulted in a significant elevation in the auditory brainstem response thresholds, a loss of auditory sensory hair cells, stereocilia degeneration and a decrease in expression of Claudin-5 and Occludin proteins at the blood-lymphatic barrier in mice. We also observed a significant decrease in the acoustic alarm response of zebrafish after exposure to polystyrene nanoplastics. Mechanistic analysis revealed that polystyrene nanoplastics induced up-regulation of the Nrf2/HO-1 pathway, increased levels of malondialdehyde, and decreased superoxide dismutase and catalase levels in cochlea and HEI-OC1 cells. Furthermore, we observed that the expression of ferroptosis-related indicators GPX4 and SLC7A11 decreased as well as increased expression of ACLS4 in cochlea and HEI-OC1 cells. This study also revealed that polystyrene nanoplastics exposure led to increased expression of the inflammatory factors TNF-α, IL-1ß and COX2 in cochlea and HEI-OC1 cells. Further research found that the cell apoptosis, ferroptosis and inflammatory reactions induced by polystyrene nanoplastics in HEI-OC1 cells was reversed through the pretreatment with N-acetylcysteine, a reactive oxygen species inhibitor. Overall, our study first discovered and systematically revealed the ototoxicity of polystyrene nanoplastics and its underlying mechanism.

Angelica gigas extract inhibits acetylation of eNOS via IRE1α sulfonation/RIDD-SIRT1-mediated posttranslational modification in vascular dysfunction.

Angelica gigas NAKAI (AG) is a popular traditional medicinal herb widely used to treat dyslipidemia owing to its antioxidant activity. Vascular disease is intimately linked to obesity-induced metabolic syndrome, and AG extract (AGE) shows beneficial effects on obesity-associated vascular dysfunction. However, the effectiveness of AGE against obesity and its underlying mechanisms have not yet been extensively investigated. In this study, 40 high fat diet (HFD) rats were supplemented with 100-300 mg/kg/day of AGE to determine its efficacy in regulating vascular dysfunction. The vascular relaxation responses to acetylcholine were impaired in HFD rats, while the administration of AGE restored the diminished relaxation pattern. Endothelial dysfunction, including increased plaque area, accumulated reactive oxygen species, and decreased nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) Ser1177 phosphorylation, were observed in HFD rats, whereas AGE reversed endothelial dysfunction and its associated biochemical signaling. Furthermore, AGE regulated endoplasmic reticulum (ER) stress and IRE1α sulfonation and its subsequent sirt1 RNA decay through controlling regulated IRE1α-dependent decay (RIDD) signaling, ultimately promoting NO bioavailability via the SIRT1-eNOS axis in aorta and endothelial cells. Independently, AGE enhanced AMPK phosphorylation, additionally stimulating SIRT1 and eNOS deacetylation and its associated NO bioavailability. Decursin, a prominent constituent of AGE, exhibited a similar effect in alleviating endothelial dysfunctions. These data suggest that AGE regulates dyslipidemia-associated vascular dysfunction by controlling ROS-associated ER stress responses, especially IRE1α-RIDD/sirt1 decay and the AMPK-SIRT1 axis.

The Role of Reactive Oxygen Species, Inflammation, and Endoplasmic Reticulum Stress Response in the Finasteride Protective Effect against Benign Prostate Hyperplasia.

PURPOSE: Benign prostate hyperplasia (BPH) is a common age-related chronic condition. Its pathogenesis involves androgen imbalance, inflammation, oxidative stress, and endoplasmic reticulum (ER) stress. This study aims to assess the protective effect of finasteride, a 5α-reductase inhibitor, against testosterone propionate (TP)-induced BPH in rats and explore its potential mechanism of action. MATERIALS AND METHODS: TP-induced BPH rats received either saline or finasteride (1 mg/kg) orally once a day for 7 weeks. Prior to sacrificing the animals, blood samples were collected. After sacrifice, prostate and tissue around the prostate were dissected from seminal vesical for further analysis. Body weight, prostate weight, dihydrotestosterone (DHT), 5α-reductase type 2 (5-AR2), and prostate-specific antigen (PSA) levels were measured. In addition, HIF-1α, VEGF, MMP-2 expressions in prostate, oxidative stress, inflammation, and ER stress responses were analyzed to understand the mechanism of action of finasteride. RESULTS: Finasteride administration inhibited prostate enlargement, DHT, 5-AR2, and PSA levels in BPH rats. Additionally, finasteride inhibited angiogenesis markers such as HIF-1α, VEGF, and MMP-2. Moreover, components of oxidative stress, inflammation, and ER stress responses were significantly regulated by finasteride treatment. CONCLUSIONS: This study suggests that finasteride prevents BPH-associated symptoms by regulating angiogenesis, reactive oxygen species, ER stress responses, and inflammation, another mechanism to explain the effect of the 5α-reductase against BPH.

Combined Treatment of Mori folium and Mori Cortex Radicis Ameliorate Obesity in Mice via UCP-1 in Brown Adipocytes.

Mori Folium (Morus alba leaf, MF) and Mori Cortex Radicis (Morus alba root cortex, MR) have been studied for their anti-obesity effects by enhancing the browning process and inhibiting adipogenesis. However, important aspects of their protective mechanisms have not been thoroughly investigated, which could aid in developing functional food. Thus, this study aims to determine the synergistic effects of MF and MR against obesity and its associated mechanisms. In an in vitro cell culture model of brown adipocytes, a 1:1 mixture of MF and MR showed a synergistic effect on the expression of brown adipocyte-specific genes, including Ucp-1, Ppargc1a, Cbp/p300-interacting transactivator (Cited), Prdm16, Tbx1, and Fgf21 compared with either MF- or MR-treated conditions. Moreover, they demonstrated the involvement of cAMP and Ca2+ in induction of brown adipocyte-specific genes. In an in vivo model using HFD-fed mice, MF/MR significantly inhibited weight gain, plasma cholesterol, LDL, TG content, fat mass, and adipocyte size. Furthermore, MF/MR inhibited morphological alteration and the expressions of fatty acid synthesis genes such as Srebp1 and Fasn in the white adipose tissue. Thermogenesis genes were recovered in the brown adipose tissue with MF/MR supplementation, indicating that MF/MR regulated adipocytic dysmetabolism where AMPK signaling is involved. In conclusion, these results suggested that MF/MR regulates brown and beige adipocyte processes, providing one of the preventive functional food/herbal medicines against obesity and its associated metabolic diseases.

Ixeris dentata and Lactobacillus gasseri media protect against periodontitis through Nrf2-HO-1 signalling pathway.

Periodontitis is an infectious inflammation in the gums characterized by loss of periodontal ligaments and alveolar bone. Its persistent inflammation could result in tooth loss and other health issues. Ixeris dentata (IXD) and Lactobacillus gasseri media (LGM) demonstrated strong antioxidant activity, which may prevent oxidative and inflammatory periodontitis. Here, IXD and LGM extracts were investigated for antioxidative activity against oral discomfort and evaluated for their synergistic effect against oxidative and inflammatory periodontitis in a mouse model. IXD/LGM suppressed pro-inflammatory cytokines like interleukin (IL)-1ß, IL-6, and TNF-α. Additionally, it reduced pro-inflammatory mediators, nitric oxide, iNOS (inducible nitric oxide synthase), and COX-2 (cyclooxygenase-2) and enhanced AKT, Nrf2, and HO-1 activation. Similarly, IXD/LGM treatment elevated osteogenic proteins and mRNAs; alkaline phosphatase, collagen type 1 (COL1), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2). Hematoxylin and Eosin (H&E) staining and micro-CT analysis confirm the positive impact of IXD/LGM on the periodontal structure and its associated inflammation. These findings demonstrate that IXD/LGM inhibits oxidative stress, periodontal inflammation, and its resultant alveolar bone loss in which Akt (also known as protein kinase B)-nuclear factor-erythroid 2-related factor 2 (Nrf2)-hemoxygenase-1 (HO-1) signaling is involved. Thus, IXD/LGM is a potential candidate against oxidative/inflammatory stress-associated periodontitis.

TMBIM6 deficiency leads to bone loss by accelerating osteoclastogenesis.

TMBIM6 is an endoplasmic reticulum (ER) protein that modulates various physiological and pathological processes, including metabolism and cancer. However, its involvement in bone remodeling has not been investigated. In this study, we demonstrate that TMBIM6 serves as a crucial negative regulator of osteoclast differentiation, a process essential for bone remodeling. Our investigation of Tmbim6-knockout mice revealed an osteoporotic phenotype, and knockdown of Tmbim6 inhibited the formation of multinucleated tartrate-resistant acid phosphatase-positive cells, which are characteristic of osteoclasts. Transcriptome and immunoblot analyses uncovered that TMBIM6 exerts its inhibitory effect on osteoclastogenesis by scavenging reactive oxygen species and preventing p65 nuclear localization. Additionally, TMBIM6 depletion was found to promote p65 localization to osteoclast-related gene promoters. Notably, treatment with N-acetyl cysteine, an antioxidant, impeded the osteoclastogenesis induced by TMBIM6-depleted cells, supporting the role of TMBIM6 in redox regulation. Furthermore, we discovered that TMBIM6 controls redox regulation via NRF2 signaling pathways. Our findings establish TMBIM6 as a critical regulator of osteoclastogenesis and suggest its potential as a therapeutic target for the treatment of osteoporosis.

Combination of Panax ginseng and Diospyros kaki Leaf Inhibits White Adipocyte Differentiation and Browning Process through AMP-Activated Protein Kinase (AMPK) Activation In Vitro and In Vivo.

Activating brown adipose tissue (BAT) and stimulating white adipose tissue (WAT) browning is a prospective obesity treatment method. Dietary components derived from plants are the most effective approach to activate BAT and promote WAT browning in rodents. This study investigated the synergistic effects of Panax ginseng (PG) and Diospyros kaki leaf (DKL) extract on adipocyte differentiation and browning, as well as the molecular mechanism underlying their beneficial effects. The administration of PG and DKL to HFD-induced obese mice significantly decreased body weight and epididymal and abdominal adipose tissue mass. In in vitro, PG inhibited the adipogenesis of 3T3-L1 adipocytes by regulating the expression of key adipogenic regulators, such as peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding protein (C/EBP)-α. In contrast, DKL negligibly influenced the adipogenesis of 3T3-L1 adipocytes but greatly increased the protein expression of UCP-1, PGC-1α, and PPARα in BAT and/or WAT. Moreover, PG and DKL inhibited adipogenesis synergistically and activated white adipocyte browning via AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) pathways. These results suggest that a combination of PG and DKL regulates adipogenesis in white adipocytes and browning in brown adipocytes by activating AMPK/SIRT1 axis. The potential use of PG and DKL may represent an important strategy in obesity management that will be safer and more effective.

NecroX Improves Polyhexamethylene Guanidine-induced Lung Injury by Regulating Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress.

Various environmental compounds are inducers of lung injury. Mitochondria are crucial organelles that can be affected by many lung diseases. NecroX is an indole-derived antioxidant that specifically targets mitochondria. We aimed to evaluate the therapeutic potential and related molecular mechanisms of NecroX in preclinical models of fatal lung injury. We investigated the therapeutic effects of NecroX on two different experimental models of lung injury induced by polyhexamethylene guanidine (PHMG) and bleomycin, respectively. We also performed transcriptome analysis of lung tissues from PHMG-exposed mice and compared the expression profiles with those from dozens of bleomycin-induced fibrosis public data sets. Respiratory exposure to PHMG and bleomycin led to fatal lung injury manifesting extensive inflammation followed by fibrosis. These specifically affected mitochondria regarding biogenesis, mitochondrial DNA integrity, and the generation of mitochondrial reactive oxygen species in various cell types. NecroX significantly improved the pathobiologic features of the PHMG- and bleomycin-induced lung injuries through regulation of mitochondrial oxidative stress. Endoplasmic reticulum stress was also implicated in PHMG-associated lung injuries of mice and humans, and NecroX alleviated PHMG-induced lung injury and the subsequent fibrosis, in part, via regulation of endoplasmic reticulum stress in mice. Gene expression profiles of PHMG-exposed mice were highly consistent with public data sets of bleomycin-induced lung injury models. Pathways related to mitochondrial activities, including oxidative stress, oxidative phosphorylation, and mitochondrial translation, were upregulated, and these patterns were significantly reversed by NecroX. These findings demonstrate that NecroX possesses therapeutic potential for fatal lung injury in humans.

Ramie leaf Extract Alleviates Bone Loss in Ovariectomized Rats-The Involvement of ROS and Its Associated Signalings.

Ramie leaf (Boehmeria nivea L.) has been traditionally used to treat gynecological and bone-related disorders. This study aims to evaluate the effect of Ramie leaf extracts (RLE) against osteoporosis in ovariectomized (OVX) rats. Female SD rats aged seven weeks were randomly assigned into five OVX and a sham-operated (sham) group. OVX subgroups include OVX, vehicle-treated OVX group; E2, OVX with 100 µg/kg 17ß-estradiol; and RLE 0.25, 0.5, and 1, OVX rats treated with 0.25, 0.5, and 1 g/kg/day RLE, respectively. Two weeks into the bilateral ovariectomy, all the rats were orally administered with or without RLE daily for 12 weeks. OVX rats administered with RLE showed higher bone density, relatively low tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and lower reactive oxygen species (ROS) within bone tissues compared to vehicle-treated OVX rats. Furthermore, supplementation of RLE improved bone mineral density (BMD) and bone microstructure in the total femur. RLE prevented RANKL-induced osteoclast differentiation and expression of osteoclastogenesis-related genes such as Cal-R, MMP-9, cathepsin K, and TRAP in RANKL-induced RAW264.7 cells. Moreover, RLE administration lowered the intracellular ROS levels by reducing NADPH oxidase 1 (NOX-1) and 4-hydroxynonenal (4HNE). These results suggest that RLE alleviates bone mass loss in the OVX rats by inhibiting osteoclastogenesis, where reduced ROS and its associated signalings were involved.

Citrus junos Tanaka Peel Extract Ameliorates HDM-Induced Lung Inflammation and Immune Responses In Vivo.

In the wake of the COVID-19 pandemic, lung disorders have become a major health concern for humans. Allergic asthma is the most prevalent form of asthma, and its treatments target the inflammation process. Despite significant developments in the diagnosis and management of allergic asthma, side effects are a major concern. Additionally, its extreme heterogeneity impedes the efficacy of the majority of treatments. Thus, newer, safer therapeutic substances, such as natural products, are desired. Citrus junos Tanaka has traditionally been utilized as an anti-inflammatory, sedative, antipyretic, and antitoxic substance. In this study, the protective effects of Citrus junos Tanaka peel extract (B215) against lung inflammation were examined, and efforts were made to understand the underlying protective mechanism using an HDM-induced lung inflammation murine model. The administration of B215 reduced immune cell infiltration in the lungs, plasma IgE levels, airway resistance, mucus hypersecretions, and cytokine production. These favorable effects alleviated HDM-induced lung inflammation by modulating the NF-κB signaling pathway. Hence, B215 might be a promising functional food to treat lung inflammation without adverse effects.

Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy.

Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment.

Turmeric extract (Curcuma longa L.) regulates hepatic toxicity in a single ethanol binge rat model.

Hepatic alcohol clearance is a key factor to overcome alcohol hangovers, and over the period, alcohol hangovers may lead to inflammation and oxidative stress. Natural food products with high antioxidant and anti-inflammatory effects might contribute to hepatic alcohol clearance, a hypothesis in this study. The present study aimed to evaluate the influence of turmeric (Curcuma longa L., Zingiberaceae) is an herbal product having antioxidant and anti-inflammatory activities, on alcohol metabolism using binge alcohol drinking rat model. In vivo investigations revealed that pretreatment with turmeric extract enhanced alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities upon binge ethanol (3 g/kg). Additionally, pretreatment with turmeric extract regulated CYP2E1 activity and levels of reactive oxygen species (ROS), Bax, Bcl-2, and inflammatory mediators like IL-1ß, IL-6, and TNF-α. Moreover, turmeric extract upregulated superoxide dismutase, catalase, and glutathione peroxidase activities in liver tissues. Together, these observations shed light on the potential beneficial effects of turmeric extract against acute liver toxicity. The results offer an alternative natural functional food product, turmeric extract, to prevent the negative implications of binge drinking.

GABA and Fermented Curcuma longa L. Extract Enriched with GABA Ameliorate Obesity through Nox4-IRE1α Sulfonation-RIDD-SIRT1 Decay Axis in High-Fat Diet-Induced Obese Mice.

Gamma-aminobutyric acid (GABA) is a natural amino acid with antioxidant activity and is often considered to have therapeutic potential against obesity. Obesity has long been linked to ROS and ER stress, but the effect of GABA on the ROS-associated ER stress axis has not been thoroughly explored. Thus, in this study, the effect of GABA and fermented Curcuma longa L. extract enriched with GABA (FCLL-GABA) on the ROS-related ER stress axis and inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) sulfonation were examined with the HFD model to determine the underlying anti-obesity mechanism. Here, GABA and FCLL-GABA supplementations significantly inhibited the weight gain in HFD fed mice. The GABA and FCLL-GABA supplementation lowered the expressions of adipogenic transcription factors such as PPAR-γ, C/EBPα, FAS, and SREBP-1c in white adipose tissue (WAT) and liver from HFD-fed mice. The enhanced hyper-nutrient dysmetabolism-based NADPH oxidase (Nox) 4 and the resultant IRE1α sulfonation-RIDD-SIRT1 decay under HFD conditions were controlled with GABA and FCLL-GABA. Notably, GABA and FCLL-GABA administration significantly increased AMPK and sirtuin 1 (SIRT1) levels in WAT of HFD-fed mice. These significant observations indicate that ER-localized Nox4-induced IRE1α sulfonation results in the decay of SIRT1 as a novel mechanism behind the positive implications of GABA on obesity. Moreover, the investigation lays a firm foundation for the development of FCLL-GABA as a functional ingredient.

d-Allulose Ameliorates Hyperglycemia Through IRE1α Sulfonation-RIDD-Sirt1 Decay Axis in the Skeletal Muscle.

Aims: The skeletal muscle maintains glucose disposal via insulin signaling and glucose transport. The progression of diabetes and insulin resistance is critically influenced by endoplasmic reticulum (ER) stress. d-Allulose, a low-calorie sugar substitute, has shown crucial physiological activities under conditions involving hyperglycemia and insulin resistance. However, the molecular mechanisms of d-allulose in the progression of diabetes have not been fully elucidated. Here, we evaluated the effect of d-allulose on hyperglycemia-associated ER stress responses in human skeletal myoblasts (HSkM) and db/db diabetic and high-fat diet-fed mice. Results: d-allulose effectively controlled glycemic markers such as insulin and hemoglobin A1c (HbA1c), showing anti-diabetic effects by inhibiting the disruption of insulin receptor substrate (IRS)-1 tyrosine phosphorylation and glucose transporter 4 (GLUT4) expression, in which the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) pathway is involved. The levels of glucose dysmetabolism-based NADPH oxidase, such as NADPH-dependent oxidoreductase (Nox) 4, were highly increased, and their interaction with IRE1α and the resultant sulfonation-regulated IRE1-dependent decay (RIDD)-Sirt1 decay were also highly increased under diabetic conditions, which were controlled with d-allulose treatment. Skeletal muscle cells grown with a high glucose medium supplemented with d-allulose showed controlled IRE1α sulfonation-RIDD-Sirt1 decay, in which Nox4 was involved. Innovation and Conclusion: The study observations indicate that d-allulose contributes to the muscular glucose disposal in the diabetic state where ER-localized Nox4-induced IRE1α sulfonation results in the decay of Sirt1, a core factor for controlling glucose metabolism. Antioxid. Redox Signal. 37, 229-245.

IBF-R Regulates IRE1α Post-Translational Modifications and ER Stress in High-Fat Diet-Induced Obese Mice.

Obesity is a global health issue linked to the heightened risk of several chronic diseases. Rhus verniciflua (RV) is a traditional food supplement used for a range of pharmacological effects such as antitumor, antioxidant, α-glucosidase inhibitory effects, hepatitis, and arthritis. Despite the traditional medicinal values, scientific evidence for its application in obesity is inadequate and unclear. Thus, this investigation was designed to evaluate the anti-obesity effects of IBF-R, an RV extract, using a high-fat diet (HFD) model. The study has six groups: chow diet group; chow diet with 80 mg/kg IBF-R; HFD group; IBF-R group with 20, 40, and 80 mg/kg. IBF-R supplementation significantly regulated the weight gain than the HFD fed mice. Further, IBF-R supplementation lowered the expressions of adipogenic transcription factors such as SREBP-1c, C/EBPα, FAS, and PPAR-γ in white adipose tissue (WAT) of diet-induced obese mice. In addition, IBF-R supplementation reduced the lipogenic gene expression while enhancing genes was related to fatty acid oxidation. Obesity is linked to redox-based post-translational modifications (PTMs) of IRE1α such as S-nitrosylation, endoplasmic reticulum (ER) stress, and chronic metabolic inflammation. The administration of IBF-R inhibits these PTMs. Notably, IBF-R administration significantly enhanced the expression of AMPK and sirtuin 1 in WAT of HFD-fed mice. Together, these findings reveal the IRE1α S-nitrosylation-inflammation axis as a novel mechanism behind the positive implications of IBF-R on obesity. In addition, it lays a firm foundation for the development of Rhus verniciflua extract as a functional ingredient in the food and pharmaceutical industries.

TMBIM6 regulates redox-associated posttranslational modifications of IRE1α and ER stress response failure in aging mice and humans.

Age-associated persistent ER stress is the result of declining chaperone systems of the ER that reduces cellular functions, induces apoptosis, and leads to age-related diseases. This study investigated the previously unknown regulatory mechanism of TMBIM6 during age-associated hepatic abnormalities. Wild-type (WT) and the TMBIM6 knockout (TMBIM6-/-) mice liver, human liver samples from different age groups were used to demonstrate the effect of physiological aging on liver. For TMBIM6 rescue experiments, TMBIM6-/- old mice and stable human hepatic cell lines expressing TMBIM 6 were used to study the functional role of TMBIM6 on aging-associated steatosis and its associated mechanisms. In aging humans and mice, we observed declined expression of TMBIM6 and aberrant UPR expression, which were associated with high hepatic lipid accumulation. During aging, TMBIM6-deficient mice had increased senescence than their WT counterparts. We identified redox-mediated posttranslational modifications of IRE1α such as S-nitrosylation and sulfonation were higher in TMBIM6-deficient aging mice and humans, which impaired the ER stress response signaling. Sulfonation of IRE1α enhanced regulated IRE1α-dependent decay (RIDD) activity inducing TMBIM6 decay, whereas S-nitrosylation of IRE1α inhibited XBP1 splicing enhancing the cell death. Moreover, the degradation of miR-338-3p by strong IRE1α cleavage activity enhanced the expression of PTP1B, resulting in diminishing phosphorylation of PERK. The re-expression of TMBIM6 reduced IRE1α modifications, preserved ER homeostasis, reduced senescence and senescence-associated lipid accumulation in human hepatic cells and TMBIM6-depleted mice. S-nitrosylation or sulfonation of IRE1α and its controller, the TMBIM6, might be the potential therapeutic targets for maintaining ER homeostasis in aging and aging-associated liver diseases.