bims-unfpre 2026-01-25 papers

JCI Insight. 2026 Jan 23. pii: e182809. [Epub ahead of print]11(2):

The critical role of GRP78/BiP MARylation in ER stress of KRAS-mutant colorectal cancer.

Shuxian Zhang, Xiaodan Chen, Qian Gong, Jing Huang, Yi Tang, Ming Xiao, Ming Li, Qingshu Li, Yalan Wang.

Nearly 50% of patients with KRAS-mutant colorectal cancer (CRC) currently lack effective targeted therapy. The accumulation of KRAS-mutant proteins can trigger a sustained high level of endoplasmic reticulum (ER) stress, and the UPR-based long-term protective regulatory pathway inhibits the aggregation of unfolded proteins, thereby maintaining the stability of the ER and enabling the continued survival of KRAS-mutant tumors. However, the critical factors that affect the regulation of ER homeostasis in KRAS-mutant CRC are still unclear. Mono-ADP ribosylation (MARylation) catalyzed by ART1 is the most important modification of GRP78/BiP and stabilizes the internal environment of the ER. In this study, KRAS mutation increased the levels of ART1, ER stress, and MARylated GRP78/BiP in CRC cells. Inhibiting MARylated GRP78/BiP can impede the downstream IRE1α/XBP1/TFAF2/JNK and PERK/eIF2α/ATF4 cascades by affecting the binding and dissociation of GRP78/BiP with receptors to hinder the growth of KRAS-mutant CRC cells and accelerate their apoptosis. We propose that KRAS-mutant CRC cells are more sensitive to intervention with MARylated GRP78/BiP because more modifications are needed to maintain ER stability. We also conducted a preliminary study on the specific site of function. Clarifying this molecular mechanism can provide a experimental basis for identifying effective targets for the intervention of KRAS-mutant CRC.

Keywords: Cell biology; Cell stress; Colorectal cancer; Gastroenterology; Oncology

DOI: https://doi.org/10.1172/jci.insight.182809

Sci Rep. 2026 Jan 21.

ATF4 regulates mitochondrial dysfunction and mitophagy, contributing to corneal endothelial apoptosis.

Saba Qureshi, Stefan Y Kim, Stephanie Lee, Lukas Ritzer, William Steidl, Gayle Joliet Krest, Anisha Kasi, Varun Kumar.

Keywords: ATF4; Cell survival; ER stress; Mitochondrial stress; Mitophagy

DOI: https://doi.org/10.1038/s41598-026-36453-x

iScience. 2026 Jan 16. 29(1): 114277

Basal level of ATF4 promotes T cell readiness for activation-induced proliferation.

Yushan Yi, Ce Luo, Jingyi Wang, Yujia Wang, Lixue Jin, Xiuyuan Sun, Jie Hao, Guoping Deng, Rong Jin, Qing Ge.

Stress-response elements are required during late-phase T cell activation and differentiation. To investigate whether they are indispensable during the first 12-24 h post-stimulation when mitochondrial activation and metabolic reprogramming are critical, we activated Atf4-sufficient and Atf4-deficient T cells and tracked their earliest activation dynamics. We demonstrate that T cell activation-induced mTOR and GCN2 phosphorylation leads to the upregulation of ATF4 protein as early as 12 h after stimulation. This early induction of ATF4 has transcriptional activities that regulate stress response, signaling, and metabolism. Loss of Atf4 in T cells alters transcriptome dynamics, impairs amino acid transport and biosynthesis, and disrupts adaptive responses to ER stress and oxidative stress, resulting in defective effector cell differentiation in vitro or in vivo. Our findings suggest that a basal level of ATF4 during the early phase of T cell activation enhances the preparedness of cells to cope with integrated stresses during the activation course.

Keywords: Cell biology; Immunology

DOI: https://doi.org/10.1016/j.isci.2025.114277

Nat Commun. 2026 Jan 22.

Camouflaged nanorobots target and regulate macrophage subcellular organelle crosstalk patterns to promote neural regeneration.

Qiangqiang Guo, Wei Wang, Xinzhao Jiang, Jincheng Tang, Feng Cai, Wenbo Wang, Lichen Zhang, Ziang Li, Yiyang Huang, Jie Wu, Liang Zhou, Haochen Jiang, Yiwei Zhu, Guhao Cai, Ziyu Lin, Yong Gu, Xuesong Zhu, Liang Chen, Kun Xi.

Macrophage (Mφ) phenotypic transformation is crucial in determining spinal cord injury (SCI) outcomes. However, the suborganelle crosstalk mechanisms-particularly between the endoplasmic reticulum (ER) and mitochondria-that mediate Mφ subgroup conversion during SCI remain underexplored. We aim to integrate niche intervention strategies and omics sequencing to investigate the effects of the metabolic crosstalk between ER stress (ERS) and mitochondria. Subsequently, we develop a dual-targeted camouflaged nanorobot (BP@D/N) that can reach the SCI site via systemic circulation and selectively interact with Mφ. We observe that Ero1α-mediated Ca2+ shuttling is an important mechanism for locking the inflammatory phenotype of Mφ. Blocking the Ero1α/MAMs/mtCa2+ axis suppresses mtDNA release and downregulates the cGAS-STING-NFκB signaling cascade, thus promoting M2 polarization and neural repair. Our study clarifies the regulatory mechanism of Mφ transformation-associated suborganelle crosstalk and offers a paradigm for reconstructing the dynamic balance of immune-neural interactions in the SCI microenvironment for effective repair. It offers a scientifically grounded and translational approach to overcoming the clinical challenge of irreversible SCI.

DOI: https://doi.org/10.1038/s41467-026-68636-5

Nat Commun. 2026 Jan 17.

A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.

Endoplasmic reticulum-associated degradation (ERAD) is a critical protein quality control mechanism that also regulates lipid metabolism and calcium homeostasis. Dysregulation of ERAD and unfolded protein response underlies diseases including cancer, neurodegenerative disorders, and metabolic syndromes. Small molecule modulators of ERAD could enable mechanistic discovery and therapeutic intervention, but few have been identified. Using a high-content screening, we discovered several ERAD-modulating compounds, including NCATS-SM0225, an ERAD inhibitor that unexpectedly binds all three isoforms of VDAC, outer mitochondrial membrane proteins enriched at mitochondria-associated membranes. This led us to discover an essential role for VDACs in ERAD and ER-phagy. NCATS-SM0225 elevates cytosolic, ER, and mitochondrial calcium through calcium influx and IP3R-MCU activity. This calcium imbalance strengthens VDAC1-IP3R coupling and activates PERK, which phosphorylates STIM1 and drives degradation of key ERAD regulators. Loss of these components amplifies PERK signaling and selectively kills cancer cells while sparing normal cells. These findings uncover a cancer-specific role of VDACs in ERAD regulation and calcium signaling, highlighting a therapeutically actionable vulnerability.

DOI: https://doi.org/10.1038/s41467-025-67816-z