bims-unfpre 2026-06-21 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–06–21
fourteen papers selected by
Susan Logue, University of Manitoba

FGF21 reduces ER stress by enhancing the unfolded protein and integrated stress responses through increased sulfide signaling.
Cell-Penetrating Peptide-Mediated Modulation of Endoplasmic Reticulum Stress: A Bioengineered and Translational Approach.
Regulation of the endoplasmic reticulum stress sensor ATF6α through multiple oxidoreductases in the ER.
PERK orchestrates an endoplasmic reticulum stress alternative splicing program via CLK1/SRSF1.
Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.
Dual IRE1 targets: Determinants of the cell fate?
Apical Proximal Tubule Fatty Acid Uptake-Generated Ceramides Cause Endoplasmic Reticulum Stress From Altered Membrane Fluidity.
The PERK-GADD45A axis is a key driver of hepatic stellate cell activation.
Exploring the immune landscape and immunotherapy relevance of ER stress-related lncRNAs in melanoma through multi-omics and explainable machine learning.
Hac1-independent functions of Ire1 drive morphogenesis in Candida albicans through distinct transcriptional programs.
Inhibition of PERK signaling suppresses tumor progression and blocks GP73-GRP78-dependent stromal activation in hepatocellular carcinoma.
Cholesterol-driven sequestration of RETREG1/FAM134B regulates ERphagy and STING1 innate immunity.
Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
Scaling covalent ligand discovery through dynamic combinatorial library-versus-proteome screening.

Cell Metab. 2026 Jun 16. pii: S1550-4131(26)00221-4. [Epub ahead of print]

FGF21 reduces ER stress by enhancing the unfolded protein and integrated stress responses through increased sulfide signaling.

Gerald Grandl, Ann-Christine König, Fabian Metzger, Arkadiusz Liskiewicz, Tanja Hefele, Shelly Nason, Aaron Novikoff, Nada Al-Refaie, Md Abdur Rahman, Ahmed Khalil, Qian Zhang, Gustav Collden, Brian Finan, Jonathan Douros, Kirk Habegger, Alberto Cebrian-Serrano, Stefanie M Hauck, Matthias H Tschöp, Timo D Müller.

  Fibroblast growth factor 21 (FGF21) is an endocrine hormone with broad metabolic actions at supraphysiological concentrations but unclear physiological function, related to endoplasmic reticulum (ER) stress. ER stress activates the unfolded protein response (UPR), a cellular repair mechanism that maintains cellular homeostasis during protein folding stress. Using proximity labeling, we assessed the intracellular action of FGF21 at its receptor β-klotho (KLB) and discovered associations with protein folding in the ER, ER stress, and H2S production. We found that FGF21 increases enzymatic sulfide production and enhances, but does not initiate, the UPR. This FGF21 action is blunted by genetic or pharmacological inhibition of sulfide signaling and is phenocopied by an H2S donor in vivo. FGF21 modulating the UPR requires KLB, and even physiological levels of FGF21 modulate the UPR via increased hepatic H2S production. Collectively, we reveal a novel physiological role of FGF21 as an endocrine stress hormone that enhances the UPR via increased sulfide signaling.

Keywords:  ER stress; FGF21; H(2)S; ISR, β-klotho, KLB; UPR; integrated stress response; sulfide signaling; unfolded protein response

DOI:  https://doi.org/10.1016/j.cmet.2026.05.011
ACS Pharmacol Transl Sci. 2026 Jun 12. 9(6): 1241-1262

Cell-Penetrating Peptide-Mediated Modulation of Endoplasmic Reticulum Stress: A Bioengineered and Translational Approach.

Tripti Paliwal, Radhika Joshi, Sarvesh Paliwal, Dipjyoti Chakraborty, Swapnil Sharma.

  Endoplasmic reticulum (ER) stress is central to the onset and progression of metabolic and inflammatory disorders, such as insulin resistance, hepatic steatosis, and cardiovascular dysfunction. The unfolded protein response, triggered by ER stress, induces maladaptive pathways through PERK, IRE1, and ATF6, leading to inflammation, apoptosis, and cellular dysfunction. Targeted ER stress modulation is an attractive therapeutic approach, and recent developments in bioengineering have enabled precise delivery of modulatory agents using cell-penetrating peptides and adipose-derived stem cells. On the one hand, cell-penetrating peptides (CPPs) enable intracellular delivery of therapeutic cargoes such as siRNA, peptides, or small-molecule targeting key ER stress mediators, including CHOP, GRP78, IRE1, and NF-κB. CPP-mediated delivery systems restore ER homeostasis, reduce inflammatory signaling, and improve cellular survival in hepatocytes, pancreatic β-cells, and cardiomyocytes. Simultaneously, adipose tissue-derived stem cells (ADSCs), which are derived from lipo-aspirated fat tissue, induce paracrine effects through the secretion of anti-inflammatory cytokines (i.e., IL-10), growth factors (i.e., VEGF, HGF, TGF-β), and antioxidants that regulate ER stress responses. ADSCs also have adipogenic and endothelial differentiation, playing roles in repairing tissue and metabolic homeostasis. Downregulation of ER stress markers and mitigation of oxidative stress increase their therapeutic efficacy for metabolic disorders. Collectively, this bioengineered synergy of CPPs and ADSCs represents a multifunctional therapeutic platform to target ER stress and its downstream effects. This synergistic approach has translational potential for precision medicine in metabolic pathophysiology, advancing from laboratory innovations to clinical applications.

Keywords:  ER stress; adipose tissue-derived stem cells; cell penetrating peptide; metabolic dysfunction

DOI:  https://doi.org/10.1021/acsptsci.5c00742
iScience. 2026 Jun 19. 29(6): 116290

Regulation of the endoplasmic reticulum stress sensor ATF6α through multiple oxidoreductases in the ER.

Shota Wada, Kaiku Uegaki, Kazuhiro Nagata, Ryo Ushioda.

  The unfolded protein response (UPR) maintains cellular homeostasis during ER stress. In this process, activating transcription factor 6α (ATF6α) is activated through several multi-step processes, including transport to the Golgi apparatus, and plays an important role as a UPR sensor. Disulfide bond-mediated dimerization of ATF6α contributes to efficient transport to the Golgi apparatus. However, this regulatory mechanism remains unclear. Here, we show that ER-resident oxidoreductases, including ERdj5 and PDIR, promote C467 dimerization, whereas ERp18 inhibits this process. In particular, ERdj5 facilitates C467 dimerization via Trx2 and reduces C618 dimerization via Trx3, supporting ATF6α activation. Furthermore, ATF6α dimerization stabilizes its structure and prevents its degradation by ER-associated degradation (ERAD). Our findings reveal that multiple oxidoreductases participate in the regulation of ATF6α activation during ER stress.

Keywords:  molecular interaction; molecular network; protein

DOI:  https://doi.org/10.1016/j.isci.2026.116290
Nat Commun. 2026 Jun 19.

PERK orchestrates an endoplasmic reticulum stress alternative splicing program via CLK1/SRSF1.

Céline Philippe, Shoshana Burke, Arantxa Carrasco-Leon, Andrea Martisova, Pedro Casado, Eleni Maniati, Jimena Castorena, Pantelitsa Protopapa, Alyssa Fronk, Ru-Pin Alicia Chi, Rachel Boniface, Vinothini Rajeeve, Martin Dodel, Beatriz Galvão, Marc Aubry, Kaliya Svetlinova Georgieva, Doriana Di Bella, Brian N Papas, Taylor Floyd, Kendall Anderson, Martin Akerman, Jun Wang, Lovorka Stojic, Faraz Mardakheh, Marcos Morgan, Eric Chevet, Christian Touriol, Pedro R Cutillas, Kevin Rouault-Pierre.

The unfolded protein response (UPR) is a critical adaptive program triggered upon cellular stresses that profoundly reshapes the transcriptome and translatome. In the very first minutes of cellular stress, translation blockage, RNA decay and RNA granules formation prompt the synthesis of proteins essential to the stress response. Due to the dynamic nature of these processes, investigating translation upon stress has proven to be challenging; therefore, our understanding of these mechanisms and translatome rewiring upon stress remains limited. Here, we exploit O-Propargyl-puromycin (OPP) labelling of de novo peptides followed by LC-MS/MS to identify de novo proteins translated upon endoplasmic reticulum (ER) stress. Combined with transcriptomic analyses, our approach reveals that ER stress profoundly impacts the synthesis of core splicing factor proteins leading to a significant reshaping of the splicing landscape. We identify a signature of seven splicing events consistently occurring in mammalian cells exposed to ER stress. Using pharmacological, genetic, phosphoproteomic and sequencing approaches, we demonstrate that this specific signature is driven by PERK activation and is dependent on the axis CLK1/SRSF1. Our findings identify PERK/CLK1/SRSF1 -mediated splicing regulation as a new facet of ER stress, defining an ERi-splice signature spanning healthy and malignant tissues.

DOI: https://doi.org/10.1038/s41467-026-74397-y
FEBS J. 2026 Jun 16.

Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.

Tony Avril, Matthieu Le Gallo, Elodie Lafont.

  The endoplasmic reticulum (ER) is a cellular organelle frequently subjected to stress under both physiological and pathological circumstances, associated with the accumulation of mis/unfolded proteins in its lumen. To cope with this stress, cells have evolved an adaptive program called the unfolded protein response (UPR), whose primary function is to restore ER proteostasis. When the stress is prolonged, the UPR can also trigger cell death. The UPR controls multiple machineries involved in pre-emptive quality control (QC) of proteins prior to ER entry, ribosome-associated QC, protein folding within the ER, protein degradation through various processes, and export from the ER for secretion. Because the UPR and the machineries it controls play fundamental roles in determining cell fate, they are finely regulated, including through post-translational modifications (PTMs). In this review, we focus on the role of the ubiquitin and ubiquitin-like PTMs in the regulation and mediation of ER proteostasis. We specifically focus on three core processes: the UPR, ER-associated ribosome QC and ER-associated degradation. Lastly, we briefly discuss how Ub and Ubl also control the integrated stress response and the formation of inter-organelle membrane contact sites and thus act as general regulators of responses to cellular stresses beyond ER proteotoxicity.

Keywords:  ER stress; ERAD; ER‐ribosomal quality control; endoplasmic reticulum; integrated stress response; ubiquitin; ubiquitin‐like; unfolded protein response

DOI:  https://doi.org/10.1111/febs.70622
FEBS J. 2026 Jun 15.

Dual IRE1 targets: Determinants of the cell fate?

Eva Billat, Léane Legrand, Tony Avril, Elodie Lafont.

  IRE1α (hereafter referred to as IRE1) is one of the sensors implicated in the unfolded protein response that controls the ER protein homeostasis (also known as proteostasis). Alteration of proteostasis is observed in many diseases, making IRE1 a central element of cell adaptability upon disease onset and progression. Upon ER stress, IRE1 initially promotes cell adaptation. Conversely, when proteostasis cannot be restored, IRE1 activation can lead to cell death. IRE1 activity mainly regulates two pathways: the formation of the transcription factor XBP1s; and the regulated IRE1-dependent decay (RIDD) of RNA, which can contribute to both cell adaptation and death. Hence, on one hand, IRE1 favors gene expression, while on the other hand it induces transcript degradation. We have recently identified two genes, CD95 and UBE2D3, which are targeted by both signaling branches downstream of IRE1 RNase's activity, resulting in a dual and opposing regulation of their expression. We propose naming these targets 'DIT' for Dual IRE1 Targets. Interestingly, other IRE1 targets, such as BiP and DGAT2, have previously been reported to be regulated by XBP1s and RIDD in separate studies. We hypothesize that regulation of DIT could be crucial to tilt the balance between the pro-adaptative and pro-death outcomes of IRE1, especially in pathological contexts. Therefore, understanding this regulation could be key to unraveling the IRE1/XBP1s/RIDD signaling network. Here, we explore these hypotheses by highlighting various aspects of the regulation of IRE1 branches, and reviewing the DIT identified in the literature so far.

Keywords:  CD95; ER stress; IRE1; RIDD; UBE2D3; XBP1s; cancer; dual IRE1 target; proteostasis

DOI:  https://doi.org/10.1111/febs.70624
JCI Insight. 2026 Jun 18. pii: e199699. [Epub ahead of print]

Apical Proximal Tubule Fatty Acid Uptake-Generated Ceramides Cause Endoplasmic Reticulum Stress From Altered Membrane Fluidity.

Zhiyu Liu, Robert J Gaivin, Shenaz Khan, Vincent Li, Amal Chaba, Fraser J Moss, Usman Sabir, Takhar Kasumov, Tingwei Mu, Jeffrey R Schelling.

  Circulating fatty acids (FA) are constitutively taken up by basolateral kidney proximal tubule transporters and are the preferred metabolic substrate. In many chronic kidney diseases, the damaged glomerular filtration barrier permits passage of albumin-bound FA, which are reabsorbed by apical FA transport protein-2 (FATP2). Bilateral FA uptake leads to lipotoxicity and progressive renal function decline, but the relative apical versus basolateral contribution and intracellular mechanisms are not established. Apical or bilateral (but not basolateral) palmitate incubation with human proximal tubule cells stimulated endoplasmic reticulum (ER) stress gene expression, ER stress pathway activation, and ER fragmentation. Apical or bilateral palmitate was associated with reduced lipid droplets, and decreased expression of ER-localized lipid droplet biogenesis transcripts. Inhibition of lipid droplet formation also precipitated ER stress, suggesting diminished sequestration of FA metabolites as the cause. Indeed, C16:0 ceramide was increased in bilateral palmitate-treated cells, and in kidneys from mice that phenocopy progressive diabetic kidney disease. Ceramide synthesis inhibition abrogated ER stress, and transfection with C16:0 ceramide decreased ER membrane fluidity and caused ER stress. We conclude that aberrant filtration and uptake of FA by apical FATP2 exceeded the capacity for lipid droplet incorporation, and led to cytotoxicity from ceramide-induced ER lipid bilayer stress.

Keywords:  Cell biology; Chronic kidney disease; Nephrology

DOI:  https://doi.org/10.1172/jci.insight.199699
Hepatol Commun. 2026 Jul 01. pii: e0980. [Epub ahead of print]10(7):

The PERK-GADD45A axis is a key driver of hepatic stellate cell activation.

Nipuni Barupala, Jagannath Misra, Emely Bibian, Reese Baxter, Vandana Singh, Noah Xique, Ethan D Goins, Alex Jackson, Scott M Ebert, Christopher M Adams, Jessica L Maiers.

   BACKGROUND: Hepatic stellate cells (HSCs) play a pivotal role in driving fibrosis during chronic liver injury. HSCs produce vast amounts of fibrotic proteins, causing endoplasmic reticulum (ER) stress and initiating the unfolded protein response (UPR). While the UPR is important for fibrogenesis, how signaling through UPR transducer Protein Kinase R-like ER Kinase (PERK) and its effectors impact HSC activation and fibrogenesis is unclear. Here, we sought to uncover the role of PERK and its effector GADD45A in liver fibrosis.
METHODS: PERK-GADD45A signaling was assessed in primary and immortalized HSCs treated with TGFβ, and mouse models of fibrosis. Genetic and pharmacological disruption of PERK or GADD45A was used to assess the role of PERK or GADD45A in HSC activation, proliferation, and fibrogenesis. HSC-specific Gadd45a-null mice were utilized to investigate the role of GADD45A on CCl4-induced fibrosis.
RESULTS: We found that TGFβ-induction of collagen I drives activation of PERK signaling in HSCs. Furthermore, loss or inhibition of PERK limits long-term HSC activation as illustrated by reduced levels of collagen I and fibronectin, impaired collagen I deposition, and reduced cell proliferation in vitro. Next, we show that PERK signaling induces expression of GADD45A during HSC activation, and loss of GADD45A disrupts HSC activation and expression of proliferation and cell-cycle-associated genes in immortalized and primary HSCs. Finally, HSC-specific GADD4Aa loss limits CCl4-driven fibrogenesis in vivo.
CONCLUSION: PERK signaling is critical for HSC activation, and loss of the PERK downstream effector GADD45A limits fibrosis progression. Disruption of HSC activation and proliferation, coupled with dysregulation of cell-cycle-associated genes upon PERK or GADD45A loss, suggests that PERK-GADD45A signaling impacts multiple facets of HSC pathophysiology.

Keywords:  HSC; TGFβ; endoplasmic reticulum stress; liver fibrosis; unfolded protein response

DOI:  https://doi.org/10.1097/HC9.0000000000000980
BMC Cancer. 2026 Jun 19.

Exploring the immune landscape and immunotherapy relevance of ER stress-related lncRNAs in melanoma through multi-omics and explainable machine learning.

Bingqian Hu, Cuiping Shi, Min Qi, Aijia Ding, Jianglin Zhang.

   BACKGROUND: Melanoma is a highly aggressive malignancy with poor clinical outcomes, and endoplasmic reticulum (ER) stress plays an important role in tumor progression, immune regulation, and therapeutic resistance. However, the prognostic significance and biological functions of ER stress-related long noncoding RNAs (ERlncRNAs) in melanoma remain largely unclear.
METHODS: We performed an integrative analysis to systematically investigate the prognostic significance and biological relevance of ERlncRNAs in melanoma by combining bulk transcriptomic analysis, single-cell RNA sequencing, explainable machine learning, and experimental validation. Transcriptomic and clinical data were obtained from the TCGA, GTEx, and GEO databases. A 13-ERlncRNA prognostic signature was established and externally validated. Survival analysis, receiver operating characteristic analysis, and nomogram evaluation were conducted to assess model performance. SHapley Additive exPlanations (SHAP) analysis was incorporated to improve the interpretability of ERlncRNA-based risk-group classification. Immune infiltration, tumor mutational burden, TIDE scores, immune checkpoint gene expression, and predicted sensitivity to selected small-molecule targeted agents were further analyzed. Functional experiments were performed to evaluate the roles of selected ERlncRNAs in melanoma cell proliferation, colony formation, migration, and apoptosis, and Western blot analysis was used to assess the expression of ER stress-related proteins following gene silencing.
RESULTS: A 13-ERlncRNA signature with stable prognostic performance was established and externally validated in melanoma cohorts. The model effectively stratified patients into high- and low-risk groups with significantly different overall survival and served as an independent prognostic predictor. SHAP analysis identified major contributors to ERlncRNA-based risk-group classification and improved model interpretability. Significant differences in immune cell infiltration, tumor mutational burden, TIDE scores, immune checkpoint gene expression, and predicted sensitivity to selected small-molecule targeted agents were observed between the two risk groups. Single-cell RNA sequencing further revealed marked heterogeneity and dynamic alterations of ER stress-related features across distinct cell populations in melanoma. Functional experiments showed that knockdown of representative ERlncRNAs inhibited melanoma cell proliferation, colony formation, and migration, while promoting apoptosis. Moreover, gene silencing was accompanied by increased CHOP expression without an obvious concomitant increase in GRP78, suggesting a shift of the ER stress response toward a pro-apoptotic state in melanoma cells.
CONCLUSIONS: This study established an interpretable ERlncRNA-based prognostic framework for melanoma and highlighted the biological and clinical relevance of ER stress-related lncRNAs. These findings provide insights into tumor heterogeneity, immune-related characteristics, and potential therapeutic stratification in melanoma, and suggest that selected ERlncRNAs may contribute to melanoma progression partly through modulation of ER stress-associated apoptotic signaling.

Keywords:  ER stress-related lncRNAs; Interpretable machine learning; Melanoma; SHAP; Single-cell RNA sequencing

DOI:  https://doi.org/10.1186/s12885-026-16356-w
J Cell Sci. 2026 Jun 17. pii: jcs.264610. [Epub ahead of print]

Hac1-independent functions of Ire1 drive morphogenesis in Candida albicans through distinct transcriptional programs.

Samuel Stack-Couture, Gabriela Nunes Marsiglio Librais, Bryan Lung, Julie Genereaux, Viola Halder, Vanessa Dumeaux, Rebecca S Shapiro, Patrick Lajoie.

  The pathogenic yeast Candida albicans relies on morphogenesis-the transition from spherical yeast to filamentous hyphal forms-for infection. While morphogenesis requires Ire1, a transmembrane protein that canonically initiates the Unfolded Protein Response (UPR) through HAC1 mRNA splicing, the specific mechanisms linking Ire1 to filamentation remain unclear. Using transcriptome analysis, we found that the Ire1-dependent transcriptional response driving morphogenesis is fundamentally distinct from the canonical UPR response to proteotoxic stress, with minimal overlap between programs. Morphogenesis is associated with only limited HAC1 splicing compared to robust splicing during proteotoxic stress, and HAC1 deletion only partially impairs filamentation, unlike the near-complete loss observed with IRE1 deletion. These findings establish that Ire1 regulates hyphal development through previously uncharacterized HAC1-independent pathways. We identify cell wall integrity as a key HAC1-independent mechanism, with Ire1-but not Hac1-essential for cell wall stress tolerance and upregulation of cell wall biosynthesis genes during filamentation. Our data also reveal Ire1-dependent decreases in transcripts encoding secretory proteins during both proteotoxic stress and morphogenesis, consistent with a possible role for Ire1-mediated mRNA degradation in these processes. Given Ire1's essential role in pathogenesis and extensive development of Ire1-targeting compounds for mammalian systems, our findings position Ire1 as a highly promising druggable target for novel antifungal therapeutics and development of fungal-specific inhibitors.

Keywords:  Candida albicans; Endoplasmic reticulum; Morphogenesis; UPR

DOI:  https://doi.org/10.1242/jcs.264610
Neoplasia. 2026 Jun 16. pii: S1476-5586(26)00059-X. [Epub ahead of print]79 101329

Inhibition of PERK signaling suppresses tumor progression and blocks GP73-GRP78-dependent stromal activation in hepatocellular carcinoma.

Jaafar Khaled, Maria Kopsida, Tania Payo Serafín, Sofi Sennefelt Nyman, Fredrik Rorsman, Charlotte Ebeling Barbier, Hans Lennernäs, Markus Sjöblom, Femke Heindryckx.

  Endoplasmic reticulum (ER) stress contributes to hepatocellular carcinoma (HCC) progression and promotes the development of a pro-tumorigenic microenvironment. Here, we demonstrate that selective inhibition of the ER-stress sensor PERK using AMG-PERK substantially restrains tumor development when administered during early carcinogenesis in a chemically induced HCC model. PERK inhibition reduced tumor burden, proliferation, and cell viability in vivo, and impaired the growth of HCC cells and patient-derived organoids in vitro. In parallel, AMG-PERK markedly reduced stromal activation, fibrosis, and inflammatory signaling within the tumor microenvironment. Mechanistic analyses indicated that ER-stress enhances tumor-stromal communication in part through increased secretion of the glycoprotein GP73, which can activate hepatic stellate cells via GRP78-dependent signaling. Blocking PERK or using GRP78-targeting antibodies reduced stellate cell activation and fibrogenic responses. Single-cell RNA sequencing and patient biopsies showed that PERK/EIF2AK3 and GP73/GOLM1 are upregulated in malignant hepatocytes and associated with poor clinical outcomes. Transcriptomic profiling further revealed that ER-stress drives oncogenic programs, including MYC signaling, epithelial-to-mesenchymal transition, and inflammatory pathway activation, all of which were affected by pharmacological PERK inhibition. Together, these findings identify PERK signaling as a potential driver of malignant progression and microenvironmental remodeling in HCC and establish PERK inhibition as a promising therapeutic strategy to target both tumor cells and their stromal interactions during the initial stages of hepatocarcinogenesis.

Keywords:  Endoplasmic reticulum stress; GP73; Hepatocellular carcinoma; PERK pathway; Tumor-stromal interactions

DOI:  https://doi.org/10.1016/j.neo.2026.101329
Autophagy. 2026 Jul;22(7): 1441-1443

Cholesterol-driven sequestration of RETREG1/FAM134B regulates ERphagy and STING1 innate immunity.

Chhabi K Govind, Daniel J Klionsky.

  The endoplasmic reticulum (ER) is a hub for several essential functions, including lipid metabolism, macroautophagy/autophagy, and innate immune signaling. Excess ER generated during a stress response is degraded by a selective type of autophagy known as ERphagy/reticulophagy. A recent study provides a mechanism by which cholesterol levels regulate ERphagy, STING1 activation, and cholesterol biosynthesis. Elevated ER cholesterol levels suppress ERphagy by reducing RETREG1/FAM134B interactions with the autophagy-related protein MAP1LC3/LC3 and the lysosomal protein LAMP2. The study shows that cholesterol directly binds to RETREG1 and SCAP, facilitating the formation of the RETREG1-SCAP complex. Sequestration of RETREG1 in this manner prevents it from performing its ERphagy functions. Furthermore, RETREG1 also interacts with STING1 and is important for its activation in response to viral infections. SCAP-RETREG1 complex formation also reduces the STING1 response. Thus, this study links lipid metabolism, innate immunity, and autophagy, emphasizing a central role for cholesterol in these processes.

Keywords:  Autophagy; ER-phagy; FAM134B/RETREG1; SCAP; STING; cholesterol

DOI:  https://doi.org/10.1080/15548627.2026.2639645
J Clin Invest. 2026 Jun 16. pii: e196687. [Epub ahead of print]

Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.

Matthew Tcheng, Veronique Voisin, Geethu Emily Thomas, Anastasija A Piric, Marcela Gronda, Rose Hurren, Dakai Ling, Yongran Yan, Lan Xin Zhang, Yue Feng, Ali Chegini, Nathan Duong, Ross S Mancini, Stefan Quinn W Currie, Zaynab Mamai, Brady Stock, Shahbaz Khan, Yulia Jitkova, Chaitra Sarathy, Edward Ayoub, Po Yee Mak, Andrea Arruda, Thomas Kislinger, Mark Reed, Bing Z Carter, Michael Andreeff, Steven M Kornblau, Mark D Minden, Siavash Vahidi, Aaron D Schimmer.

  Most mitochondrial proteins are nuclear encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import is increased in acute myeloid leukemia (AML) cells compared to normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with increased mitochondrial unfolded protein response (UPRmt), a stress activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPRmt protease LONP1 (Lon Peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPRmt. Genetically or chemically inhibiting the LONP1 ATPase domain induced mitochondrial protein aggregation and selectively killed AML cells with high LONP1 expression while sparing AML cells with low LONP1 expression and normal hematopoietic cells in vitro and in vivo. Thus, we uncovered a critical role of the UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.

Keywords:  Cancer; Cell biology; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI196687
Nat Commun. 2026 Jun 19.

Scaling covalent ligand discovery through dynamic combinatorial library-versus-proteome screening.

Yuchen Huang, Lexuan Hou, Ruiping He, Lin Zhu, Caifeng Xu, Shixiang Duan, Jing Hu, Xi Yang, Yu-Hsuan Tsai, Chu Wang, Chunmao He, Xiaoyu Li, Li Chen, Gang Li.

Mass spectrometry-based chemical proteomics enables unbiased assessment of ligand potency and selectivity across the proteome. However, current approaches remain limited by the low throughput of single-compound screening and reliance on pre-synthesized libraries. Here we devise a mechanism-driven "library-versus-proteome" platform that couples dynamic combinatorial libraries with activity-based protein profiling, enabling real-time selection and optimization of ligands in complex biological systems. This approach increases screening throughput by 10- to 20-fold, streamlines library generation, and adopts a "screen first, synthesize later" paradigm. Applying this platform, we discover covalent inhibitors of serine hydrolases including PPME1, ABHD11 and PNPLA6, and reveal uncharacterized roles of PNPLA6 in lipid metabolism and cancer cell proliferation. We further extend the strategy to cysteine-targeting ligands by designing tailored warheads, enabling proteome-wide EC50 profiling of over 2600 ligandable cysteines and yielding inhibitors for NIT2, PRDX5, TXNDC17 and VCP. Focusing on VCP, we uncover a previously unrecognized signaling axis in which GPCR activity modulates activation of the ER stress-induced unfolded protein response. Using a gel-based "library-versus-proteome" assay, we screen over 800 analogues within two days and identify a more potent VCP ligand with nanomolar activity and in vivo antitumor efficacy. This work establishes library-versus-proteome screening as a scalable strategy for ligand discovery.

DOI: https://doi.org/10.1038/s41467-026-74672-y