bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–08–02
thirteen papers selected by
Susan Logue, University of Manitoba
  1. Autophagy prevents ER stress-induced Tight Junction barrier disruption via claudin-2 homeostasis.
  2. PGC-1α mediates ER stress-driven apoptotic signaling during gemfibrozil treatment in glioblastoma.
  3. Faf2 is required for neural differentiation in embryonic neural progenitor cells.
  4. DNAJB12/14 redox switching directs chaperone- and Bax/Bak-dependent ER protein reflux.
  5. Regulatory Mechanisms of XBP1 in Tumorigenesis and Cancer Progression: Challenges and Therapeutic Strategies.
  6. Hexosamine Pathway Disruption by GFPT1 Loss Drives Coordinated Defects in Glycosylation, Autophagy, and Trafficking.
  7. A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer.
  8. Oridonin targets PRDX1 to promote apoptosis by inducing ROS-mediated ER stress and modulating autophagy.
  9. Endoplasmic reticulum autophagy in inflammatory diseases.
  10. Trr1 (thioredoxin reductase 1) modulates ERphagy in aging via liquid-liquid phase separation.
  11. ER-localized translational control as a nexus for proteostasis.
  12. Subcellular Regulation of Ferroptosis: Roles of Individual Intracellular Organelles and Crosstalk.
  13. A comprehensive map of missense trafficking variants in rhodopsin and their response to pharmacologic correction.
  1. bioRxiv. 2026 Jul 20. pii: 2026.07.15.738672. [Epub ahead of print]
    Autophagy prevents ER stress-induced Tight Junction barrier disruption via claudin-2 homeostasis.
    Priya Arumugam, Kushal Saha, Ashwinkumar Subramenium Ganapathy, Alexandra Wang, Leonard Harris, Gregory Yochum, Prashant Nighot.
      Defective intestinal epithelial tight junction (TJ) barrier function and endoplasmic reticulum (ER) stress are central pathological features of inflammatory bowel disease (IBD), yet the molecular mechanisms ER stress to TJ disruption remains poorly understood. Here, we investigated the role of autophagy in regulating intestinal TJ homeostasis during ER stress. ER stress was elevated in inflamed Crohn's disease tissue and chronic dextran sulfate sodium (DSS) colitis. In human intestinal epithelial Caco-2 monolayers, murine colon, and human colonic explants, induction of ER stress with tunicamycin, thapsigargin, or brefeldin A disrupted TJ barrier integrity, as demonstrated by reduced transepithelial electrical resistance and increased paracellular permeability. ER stress selectively increased the pore-forming TJ protein claudin-2 and altered occludin localization without significantly affecting other claudins. Pharmacologic activation of autophagy with rapamycin attenuated ER stress, restored TJ barrier function, reduced claudin-2 accumulation, and preserved occludin localization. Conversely, CRISPR-Cas9-mediated deletion of autophagy gene ATG7 exacerbated ER stress, apoptosis, and TJ barrier dysfunction in vitro, while intestinal epithelial-specific Atg7 knockout mice exhibited enhanced ER stress-induced intestinal permeability in-vivo. Mechanistically, prolonged ER stress impaired autophagic flux through IRE1α kinase signaling, resulting in accumulation of p62 and claudin-2. Inhibition of IRE1α kinase activity restored autophagy, reduced claudin-2 levels, and preserved TJ barrier function. We further identified adaptor-associated kinase 1 (AAK1) as a downstream mediator of IRE1α signaling during ER stress, with increased AP2M1 phosphorylation and altered claudin-2 trafficking. Claudin-2 overexpression alone induced ER stress and lysosomal damage, suggesting a feed-forward mechanism amplifying epithelial injury. Finally, enteric rapamycin administration reduced ER stress and restored autophagy in murine DSS colitis. Collectively, these findings identify an IRE1α-AAK1-autophagy axis as a critical regulator of intestinal TJ barrier integrity during ER stress.
    DOI:  https://doi.org/10.64898/2026.07.15.738672
  2. Eur J Pharmacol. 2026 Jul 28. pii: S0014-2999(26)00660-6. [Epub ahead of print]1031 179178
    PGC-1α mediates ER stress-driven apoptotic signaling during gemfibrozil treatment in glioblastoma.
    Smita Dey, Harsha Valluri, Mukul Srivastava, Rajdeep Chowdhury, Sudeshna Mukherjee, Shibasish Chowdhury.
      Glioblastoma (GBM) is a highly aggressive and therapy-resistant brain tumor. In our earlier study, we demonstrated that the antihyperlipidemic drug Gemfibrozil, when repurposed, exerts strong cytotoxic effects on GBM cells by modulating autophagy. In the present study, we further investigated the complex interplay among key homeostatic pathways, specifically autophagy, endoplasmic reticulum (ER) stress, and calcium signalling, following Gemfibrozil exposure in the context of GBM progression and treatment resistance. Our findings reveal that Gemfibrozil-induced inhibition of autophagy triggers the unfolded protein response (UPR), leading to activation of ER stress pathways, as evidenced by altered expression of canonical markers, including IRE1α, PERK, and CHOP. Notably, CHOP silencing reduced levels of cleaved Caspase-3 and Caspase-9, confirming the involvement of ER stress-mediated apoptosis following disruption of autophagy. Moreover, the induction of ER stress and inhibition of autophagy were accompanied by disturbances in calcium homeostasis, demonstrated by reduced expression of the calcium-binding proteins Calmodulin and Calreticulin. This imbalance resulted in mitochondrial calcium overload, loss of mitochondrial membrane potential, and elevated reactive oxygen species (ROS) production, ultimately culminating in caspase activation and cell death. Mechanistically, PGC-1α emerged as a key regulator of Gemfibrozil-mediated anti-tumor activity. Collectively, our findings uncover a critical molecular cascade involving suppression of autophagy, induction of ER stress, calcium dysregulation, mitochondrial dysfunction, and oxidative stress that drives GBM cell death. These insights not only highlight Gemfibrozil as a potential therapeutic agent but also emphasize the importance of targeting homeostatic vulnerabilities in GBM.
    Keywords:  Calcium signalling; Cellular homeostasis; ER stress; Gemfibrozil; Glioblastoma multiform; PGC1α
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179178
  3. bioRxiv. 2026 Jul 13. pii: 2026.07.12.737973. [Epub ahead of print]
    Faf2 is required for neural differentiation in embryonic neural progenitor cells.
    Anneke Dixie Kakebeen, Leon Dunphy, Heather K Hazen, Lee A Niswander.
      Neural progenitor cell differentiation is a complex process requiring the proper integration of instructive and permissive factors. Instructive cues including signaling molecules and transcription factor networks have been well studied in this context, but permissive factors such as cell homeostasis have not. Cell homeostasis is critical to support the health and stability of a cell and enable the cell to act on instructive differentiation cues. Our study investigates a homeostasis protein, FAF2, and its function in neural progenitor cells. FAF2 is an adaptor protein involved in endoplasmic reticulum (ER) associated degradation to remove misfolded proteins and restore ER homeostasis. Here we show that knocking out Faf2 in neural progenitor cells results in increased ER stress signature at the protein and transcription level, indicating a conserved functional role in neural progenitor cells. Induced neural differentiation of FAF2 deletion cells shows a failure of neurite development but RNA-seq indicates genes that support neural differentiation are induced. Reducing ER stress in FAF2 knockout cells with a small molecule inhibitor can rescue neural differentiation, providing evidence that excess ER stress contributes to the inhibited differentiation. Taken together, these results reveal that FAF2 is a critical protein in neural progenitor cells for the maintenance of ER homeostasis and execution of neural differentiation.
    Highlights: FAF2 is required to regulate ER homeostasis in neural progenitor cellsFAF2 knockout blocks differentiation of neural progenitor cells to neurons at the cell morphological level, but does not inhibit the mounting of transcriptional programs associated with neural differentiation.Excess ER stress due to FAF2 knockout contributes to blocked neural differentiation.
    DOI:  https://doi.org/10.64898/2026.07.12.737973
  4. Redox Biol. 2026 Jul 25. pii: S2213-2317(26)00323-X. [Epub ahead of print]96 104324
    DNAJB12/14 redox switching directs chaperone- and Bax/Bak-dependent ER protein reflux.
    Laila Abu Madegam, Noa Gavriel, Raifu Tolulope Adebisi, Aeid Igbaria.
      Maintenance of endoplasmic reticulum (ER) proteostasis is essential for cellular homeostasis and survival during stress. Beyond canonical quality control pathways, ER-to-cytosol signaling (ERCYS) enables the reflux of ER-resident proteins into the cytosol, where they can acquire noncanonical functions that promote cell survival. However, the mechanisms governing ERCYS and its relationship to ER stress remain poorly understood. Here, we show that ER protein reflux is restricted to a defined stress window and is governed by the ER redox environment. Mild ER stress maximizes protein reflux, whereas severe or reductive stress markedly suppresses this process. Mechanistically, we identify the ER-resident cochaperones DNAJB12 and DNAJB14 as redox-sensitive regulators of ERCYS. Under mild stress, intramolecular disulfide bonds stabilize DNAJB12 and DNAJB14, thereby supporting efficient protein reflux. In contrast, severe or reductive stress increases intracellular glutathione, reducing these disulfide bonds and promoting degradation of DNAJB12 and DNAJB14, resulting in the loss of chaperone-mediated reflux. We further show that protein reflux requires cysteine-dependent interactions between refluxed substrates and the cytosolic cochaperone SGTA, revealing a previously unrecognized redox-sensitive step in the ERCYS pathway. When ERCYS is impaired during severe ER stress, cells instead engage an alternative apoptosis-associated pathway mediated by BAX/BAK-dependent ER membrane permeabilization. This transition is driven by enhanced recruitment of BAX and BAK to the ER by the BH3-only protein BIK, amplifying apoptotic signaling. Together, these findings establish redox regulation as a molecular switch that determines whether cells mount an adaptive ER protein reflux response or commit to BAX/BAK-dependent ER membrane permeabilization and apoptosis.
    DOI:  https://doi.org/10.1016/j.redox.2026.104324
  5. Pharmaceuticals (Basel). 2026 Jun 26. pii: 993. [Epub ahead of print]19(7):
    Regulatory Mechanisms of XBP1 in Tumorigenesis and Cancer Progression: Challenges and Therapeutic Strategies.
    Haiyan Jiang, Zhanzhan Li, Jie Wang, Hualin Sun, Lei Qi.
      Endoplasmic reticulum (ER) stress is a common state of cellular adversity experienced by tumor cells under unfavorable conditions such as hypoxia, nutrient deprivation, and oncogene activation. As the most conserved signaling branch of the unfolded protein response (UPR), the inositol-requiring enzyme 1α (IRE1α)- X-box-binding protein 1 (XBP1) pathway plays a central role in sustaining tumor cell survival, driving malignant progression, and remodeling the tumor microenvironment (TME). XBP1, the terminal transcription factor of this pathway, finely orchestrates tumor cell fate through both its canonical and non-canonical functions. This review systematically summarizes the dual mechanisms of XBP1 in cancer: within cancer cells, XBP1 promotes proliferation, metastasis, and chemoresistance via metabolic reprogramming, anti-apoptotic proteins, and DNA repair; within immune cells (macrophages, dendritic cells, T cells), XBP1 fosters an immunosuppressive microenvironment, while also modulating cancer-associated fibroblasts, endothelial cells, and osteoclasts. Despite its therapeutic promise, several major unresolved questions remain, including the precise molecular switch governing XBP1's pro-tumorigenic versus anti-tumorigenic functions, the functional divergence between XBP1u and XBP1s isoforms in different cellular contexts, and the lack of reliable predictive biomarkers for patient stratification. Key translational challenges involve the on-target toxicity of systemic XBP1/IRE1α inhibition due to its essential roles in normal tissues, the cell-type-specific and context-dependent effects that complicate therapeutic outcomes, and the limited selectivity and off-target effects of current inhibitors, as well as compensatory activation of other UPR branches that may drive adaptive resistance. Finally, this review discusses XBP1-targeted therapeutic strategies, including small-molecule inhibitors, nucleic acid-based drugs, immunotherapeutic combination approaches, and XBP1-based tumor vaccines, and provides perspectives on future research directions, aiming to establish a theoretical foundation for the development of more effective and precise XBP1-targeted therapies for tumorigenesis and cancer progression.
    Keywords:  XBP1; endoplasmic reticulum stress; immunosuppression; targeted therapy; therapeutic resistance; tumor microenvironment
    DOI:  https://doi.org/10.3390/ph19070993
  6. Biomolecules. 2026 Jun 30. pii: 966. [Epub ahead of print]16(7):
    Hexosamine Pathway Disruption by GFPT1 Loss Drives Coordinated Defects in Glycosylation, Autophagy, and Trafficking.
    Stephen H Holland, Ricardo Carmona-Martinez, Andreas Hentschel, Alexa Derksen, Kaela O'Connor, Daniel O'Neil, Kelly Ho, Stephen D Baird, Andreas Roos, Sally Spendiff, Hanns Lochmüller.
      Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), provides the UDP-N-acetylglucosamine (UDP-GlcNAc) required for protein glycosylation. Biallelic mutations in GFPT1 cause congenital myasthenic syndromes (GFPT1-CMS), yet the molecular mechanisms linking impaired glycosylation to skeletal muscle dysfunction remain incompletely understood. Here, we combine cellular models of inducible Gfpt1 knockdown and a skeletal muscle-specific Gfpt1 knockout mouse (Gfpt1Tm1d/Tm1d) with whole-cell proteomics, immunoblot studies and secretomics to define glycosylation-dependent defects in intracellular trafficking, ER stress signaling and autophagy. Global proteomic profiling of Gfpt1-deficient myoblasts revealed marked downregulation of protein trafficking pathways and impaired secretion of key muscle cargo proteins, including serglycin (Srgn). Loss of GFPT1 reduced both high-molecular-weight glycosylated serglycin and its core protein, accompanied by intracellular retention and decreased secretion. These trafficking defects coincide with robust activation of the unfolded protein response (UPR), evidenced by increased Xbp1 expression and accumulation of spliced Xbp1s across pharmacologic, cellular, and mouse models of GFPT1 deficiency. Converging evidence from proteomics, immunoblotting, and immunofluorescence demonstrated impaired autophagy, including increased LC3-II accumulation, elevated p62/Sqstm1 levels, and enhanced p62-positive puncta in both Gfpt1-deficient C2C12 myoblasts and skeletal muscle. Soluble/insoluble fractionation further confirmed p62 accumulation, indicating defective autophagic flux and buildup of aggregated cargo. Together, these findings identify a glycosylation-dependent failure in protein trafficking that triggers ER stress, UPR activation, and autophagy impairment in Gfpt1-deficient skeletal muscle. This mechanistic cascade provides a unifying explanation for muscle pathology in GFPT1-CMS and suggests that restoring glycosylation or improving proteostasis may represent viable therapeutic approaches.
    Keywords:  GFPT1; autophagy; congenital myasthenic syndrome; glycosylation; trafficking
    DOI:  https://doi.org/10.3390/biom16070966
  7. bioRxiv. 2026 Jun 18. pii: 2026.06.15.732391. [Epub ahead of print]
    A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer.
    Yang Zheng, Caleb Cheng, Yizhi Cao, Gabriel Cruz, Yuping Zhang, Radha Paturu, Somnath Mahapatra, Jing Hu, Rahul Mannan, Hüseyin Karabürk, Rupam Bhattacharyya, Yitong Yin, Yi Zhao, Wenyan Liu, Xuhong Cao, Hui Xue, Chungen Li, Zhen Wang, Stephanie J Miner, Ulka Vaishampayan, Vaibhav Sahai, Lois S Weisman, Ke Ding, Costas A Lyssiotis, Yuzhuo Wang, Yuanyuan Qiao, Arul M Chinnaiyan.
      Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-lipid kinase axis that drives adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, leading to ER stress accumulation and activation of a compensatory, sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.
    Keywords:  ER stress; PIKfyve; lipid metabolism; lysosome; neuroendocrine prostate cancer
    DOI:  https://doi.org/10.64898/2026.06.15.732391
  8. Int J Biol Sci. 2026 ;22(12): 6363-6380
    Oridonin targets PRDX1 to promote apoptosis by inducing ROS-mediated ER stress and modulating autophagy.
    Ziyang Ding, Sisi Wang, Junhui Chen, Yali Song, Zhou Zhu, Haibo Tong, Ashok Iyaswamy, Peng Chen, Xu Wei, Wei Zhang, Jigang Wang, Chuanbin Yang, Yulin Feng.
      Oridonin is a bioactive diterpenoid derived from the widely used traditional Chinese medicinal herb Rabdosia rubescens, exhibits broad-spectrum anti-cancer activity, with several derivatives currently in clinical trials. However, the molecular mechanism underlying its anticancer effects, especially its direct target proteins, remain to be fully elucidated. Here, we found that Oridonin promoted intracellular reactive oxygen species (ROS) accumulation, which in turn induced endoplasmic reticulum (ER) stress-mediated apoptosis. Moreover, ER stress was instrumental in inducing autophagy after Oridonin treatment, while blockade of autophagy further exacerbated Oridonin-induced cytotoxicity. Notably, using activity-based protein profiling (ABPP), we identified the anti-oxidant enzyme Peroxiredoxin 1 (PRDX1) as a key direct covalent target of Oridonin. By binding to Cysteine 173 of PRDX1, Oridonin increased intracellular ROS levels. Furthermore, PRDX1 over-expression mitigated, whereas PRDX1 knockdown potentiated, Oridonin-induced ROS accumulation, autophagy, and subsequently apoptosis. Overall, our results indicate that PRDX1 is a direct covalent binding target mediating Oridonin-induced apoptosis. These findings not only provide fresh insights into the core mechanism of Oridonin-induced cytotoxicity, but also highlight PRDX1 as a potential therapeutic target for renal cancer drug development.
    Keywords:  ER stress; autophagy; chemical proteomics; drug targets; oridonin; oxidative stress
    DOI:  https://doi.org/10.7150/ijbs.110208
  9. Front Immunol. 2026 ;17 1822159
    Endoplasmic reticulum autophagy in inflammatory diseases.
    Chunxiao Wang, Jing Gao, Changsheng Guo, Qi Li, Feixiao Wang, Ming Zhang.
      The endoplasmic reticulum (ER) is responsible for the synthesis, modification, and folding of various intracellular proteins. Under strong external stimuli, the ER often undergoes significant structural disorganization and functional abnormalities, a process that generally accelerates the onset and progression of inflammatory responses and related diseases, such as infections and sepsis, digestive system diseases, cancer, neurological disorders, circulatory diseases, and musculoskeletal diseases. Therefore, maintaining ER homeostasis is crucial for delaying the inflammatory process. As an important type of selective autophagy, ER-phagy has transcended merely "waste removal" to become a key cellular hub integrating immune and stress signals. It not only effectively curbs the excessive activation of the NF-κB pathway and the NLRP3 inflammasome by timely clearing inflammatory pathogens and ER fragments damaged by calcium store abnormalities and oxidation but also maintains immune cell homeostasis, thereby inhibiting the initiation and spread of excessive inflammatory responses. This review summarizes the key receptors, regulatory mechanisms, and the latest research on ER-phagy in various inflammation-related diseases, aiming to draw academic attention to the important value of ER-phagy in inflammatory diseases.
    Keywords:  ER stress; ER-associated degradation; ER-phagy; endoplasmic reticulum; inflammation; unfolded protein response
    DOI:  https://doi.org/10.3389/fimmu.2026.1822159
  10. Autophagy. 2026 Jul 31. 1-18
    Trr1 (thioredoxin reductase 1) modulates ERphagy in aging via liquid-liquid phase separation.
    Yuan Gao, Jingyi Zhao, Xiangdong Hu, Per Sunnerhagen, Beidong Liu.
      Aging is associated with the deterioration of various biological processes including disrupted proteostasis and impaired macroautophagy/autophagy. Biomolecules can undergo liquid-liquid phase separation (LLPS) to form biomolecular condensates that exert specific biological functions. Trr1 (thioredoxin reductase 1) is a pivotal enzyme in the thioredoxin antioxidant system. Deletion of TRR1 results in impaired autophagy; however, the underlying mechanism is largely unexplored. In this study, we explored whether LLPS of Trr1 affected autophagy. Trr1 formed dynamic LLPS condensates during replicative aging in yeast. Phase separation of Trr1 occurred in response to endoplasmic reticulum (ER) stress generated by cellular aging, rather than to oxidative stress. Furthermore, Trr1 condensates participated at the phagophore assembly site during endoplasmic reticulophagy and promoted autophagosome development by affecting lipidation of the Atg8 protein. Additionally, maintaining the liquid-like dynamic nature of Trr1 condensates was essential for cellular fitness. Our findings revealed an unconventional role of Trr1 through LLPS in aging. The function of phase-separated condensates of Trr1 in mitigating aging-associated ER stress offers insights into the mechanisms underlying healthy cellular aging. These findings highlight a potential target for developing interventions to combat aging and associated diseases.Abbreviations: Atg: autophagy related; DTT: dithiothreitol; ER: endoplasmic reticulum; ERAD: endoplasmic reticulum-associated degradation; ERphagy: endoplasmic reticulophagy; FRAP: fluorescence recovery after photobleaching; GFP: green fluorescent protein; LLPS: liquid-liquid phase separation; PAS: phagophore assembly site; PLDs: prion-like domains; RFP: red fluorescent protein; RLS: replicative lifespan; Trr1: thioredoxin reductase 1; Trx: thioredoxin; UPR: unfolded protein response; IDRs: intrinsically disordered regions.
    Keywords:  Aging; ERphagy; endoplasmic reticulum stress; liquid-liquid phase separation; thioredoxin reductase 1
    DOI:  https://doi.org/10.1080/15548627.2026.2702873
  11. FEBS J. 2026 Jul 27.
    ER-localized translational control as a nexus for proteostasis.
    Hideki Nishitoh, Hisae Kadowaki.
      Maintenance of proteostasis is essential for cellular and organismal homeostasis, and disruption of protein quality control (QC) networks underlies numerous human diseases. The endoplasmic reticulum (ER) functions as a central organelle for the synthesis, folding, maturation, and trafficking of secretory and membrane proteins, and serves as a central hub of intracellular proteostasis. Recent studies have established that the ER membrane serves not only as a site of protein translocation but also as a dynamic platform integrating translational regulation, RNA surveillance, and multiple QC pathways. During ER-associated translation, cells continuously monitor ribosome dynamics, mRNA integrity, nascent-chain folding, and transmembrane protein insertion processes to prevent the accumulation of aberrant proteins. These surveillance systems include the PKR-like ER kinase (PERK)-mediated integrated stress response (ISR), regulated IRE1-dependent decay (RIDD), nonsense-mediated mRNA decay (NMD), RNA silencing, ribosome-associated QC (RQC), ubiquitin-fold modifier 1 conjugation (UFMylation), ER-phagy, and ER stress-induced pre-emptive QC (ERpQC). Although these pathways were originally characterized independently, increasing evidence indicates that they function cooperatively on or near the ER membrane to coordinate translational attenuation, mRNA degradation, ribosome recycling, nascent-chain elimination, and organelle remodeling. In particular, UFMylation has emerged as a central mechanism linking ER-associated RQC, translocation-associated QC (TAQC), and ER-phagy. Dysfunction of these ER-localized translational QC pathways contributes to neurodegeneration, inflammation, fibrosis, cancer, and aging-related disorders. In this review, we summarize recent advances in ER-localized translational control and discuss how integrated QC networks on the ER membrane maintain proteostasis and influence disease pathogenesis.
    Keywords:  ER stress; ER stress‐induced pre‐emptive quality control; UFMylation; endoplasmic reticulum; proteostasis; ribosome‐associated quality control; translational control
    DOI:  https://doi.org/10.1111/febs.70665
  12. Am J Physiol Cell Physiol. 2026 Jul 29.
    Subcellular Regulation of Ferroptosis: Roles of Individual Intracellular Organelles and Crosstalk.
    Chanon Piamsiri, Judith K Gwathmey, Lai-Hua Xie.
      Ferroptosis is an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation. Emerging evidence indicates that susceptibility to ferroptosis is not governed solely by cytosolic signaling pathways, but instead results from the coordinated actions of multiple intracellular organelles, including mitochondria, lysosomes, the endoplasmic reticulum (ER), and lipid droplets. Mitochondria play dual roles in ferroptosis by integrating metabolic activity, redox balance, and mitochondrial quality control; thereby influencing reactive oxygen species generation and lipid peroxidation. Lysosomes regulate ferroptotic sensitivity through iron mobilization, inter-organelle iron transfer, lysosomal redox activity/lipid peroxidation, lysosomal signaling hub, and ferritinophagy. The ER contributes to ferroptosis by coordinating lipid biosynthesis, membrane polyunsaturated fatty acid composition, and unfolded protein response signaling, as well as by disrupting antioxidant defenses and iron homeostasis, especially during ER stress. Lipid droplets function as dynamic lipid reservoirs that buffer oxidizable fatty acids or, upon mobilization, supply substrates that fuel ferroptosis-associated lipid peroxidation. Here, we provide a comprehensive review of current mechanistic insights and recent advances in organelle-specific regulation and inter-organelle crosstalk during ferroptosis, highlighting emerging therapeutic opportunities and key experimental challenges. An integrated understanding of this multi-organelle regulatory network is essential for modulating ferroptosis in human diseases.
    Keywords:  Endoplasmic/Sarcoplasmic Reticulum; Ferroptosis; Lipid droplet; Lysosome; Mitochondria
    DOI:  https://doi.org/10.1152/ajpcell.00334.2026
  13. Sci Adv. 2026 Jul 31. 12(31): eaef3518
    A comprehensive map of missense trafficking variants in rhodopsin and their response to pharmacologic correction.
    Kannan V Manian, Connor H Ludwig, Yan Zhao, Nathan S Abell, Robert Warneford-Thomson, Henry Chan, Zachary O Casey, Xiaoping Yang, David E Root, Matthew L Albert, Jason Comander.
      Rhodopsin (RHO) missense variants are a leading cause of autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration. Interpreting RHO variant pathogenicity is challenging, and understanding their disease mechanisms is essential for developing therapeutics. We present a high-resolution map of RHO missense variant trafficking using deep mutational scanning approaches, including a surface abundance immunoassay and a complementary membrane proximity assay. This comprehensive, reproducible dataset encompassed all 6612 possible missense variants. Over 700 variants had pathogenic trafficking scores, substantially expanding the number of RHO variants with functional data. Trafficking scores correlated with the magnitude of ER stress markers and ClinVar pathogenicity classifications. Data also identified structurally clustered mutational intolerance around the intradiscal beta-plug region. Treatment with the chaperone YC-001 restored surface trafficking in most mistrafficking variants. This functional map of RHO variants provides a valuable resource for pathogenicity assessment, genotype-phenotype correlations, and the development of targeted therapeutic strategies for RHO-adRP.
    DOI:  https://doi.org/10.1126/sciadv.aef3518
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒02 at 1:17.