http://www.cell-stress.com The Journal of the European Research Institute for Integrated Cellular Pathology Mon, 13 Jul 2026 06:41:35 +0000 eng hourly 60 https://wordpress.org/?v=6.3.8 http://www.cell-stress.com/researcharticles/2026a-chen-cell-stress/ Tue, 07 Jul 2026 06:41:21 +0000 Cell Stress https://www.cell-stress.com/?post_type=researcharticles&p=9769
Ziqi Chen, Jie Zhang, Jianting Lao, Chaoqin Yu and Hong Yang

Triptolide, an extract from the Chinese herb Thunder God Vine, a compound renowned for its anti-cancer properties, exhibits an elusive mechanism of action. While extensive research has elucidated its direct effects on cancer cells, the indirect impact on non-tumor cells within the cancer microenvironment remains poorly understood. In this study, we investigated the influence of Triptolide on tumor-associated macrophages (TAMs), pivotal contributors to ovarian cancer progression. Using cell culture and promoter assay, cellular viability assessment, cell clock assay, transwell assays, flow cytometry, ELISA, TUNEL staining, and mouse models, we found that Triptolide does not significantly affect macrophage proliferation or survival; instead, it induces differentiation of naive macrophages towards the M1 phenotype and reprograms M2- polarized macrophages into a similar inflammatory state. These observations suggest that modulation of TAMs may partially underlie Triptolide’s hindrance of ovarian cancer progression. Mechanistically, we reveal that Triptolide inhibits Nrf2 transcription – a master regulator governing antiinflammatory responses in macrophages. Functional gain- and loss-offunction studies further confirmed that Nrf2 inhibition is essential for Triptolide-mediated TAM reprogramming and subsequent suppression of cancer cell progression. Co-culturing with macrophages substantially enhances ovarian cancer cell growth, invasion, and migration; however, all these effects are abrogated by treatment with Triptolide. Collectively, our findings indicate that the suppression of ovarian cancer by Triptolide is mediated in part through its capacity to reprogram TAMs via the Nrf2 pathway. ]]> http://www.cell-stress.com/researcharticles/2026a-madeo-cell-stress/ Fri, 03 Jul 2026 18:11:41 +0000 Cell Stress https://www.cell-stress.com/?post_type=researcharticles&p=9761
Frank Madeo, Didac Carmona-Gutierrez and Guido Kroemer

Geroprotection aims at extending healthspan by delaying age-associated pathologies. Polyamines including spermine and spermidine are interconvertible metabolites whose longevity-promoting effects have traditionally been attributed to autophagy induction. In addition, recent evidence identifies spermine as an endogenous Fe2+ chelator that suppresses ferroptosis, thereby complementing the autophagy-inducing activity of spermidine. Indeed, spermidine inhibits EP300 acetyltransferase activity and supports hypusination-dependent activation of TFEB, both leading to autophagy. However, enhanced autophagic flux may increase susceptibility to ferroptosis through ferritinophagy and lipid remodeling. In parallel, polyamine catabolism generates H2O2 and acrolein, both of which facilitate lipid peroxidation and ferroptotic demise. The discovery that spermine directly chelates redox-active Fe2+ closes a conceptual gap by explaining how polyamine supplementation can promote longevity while avoiding excessive ferroptotic cell loss. Multiple lines of evidence including metabolomics, isotope tracing, cell-free lipid peroxidation systems, Fe2+-binding biophysics, mass spectrometry, Raman spectroscopy, nuclear magnetic resonance and disease models demonstrate that spermine limits labile iron and ferroptosis. Together, these findings support a unified model in which spermidine-driven autophagy and spermine-mediated ferroptosis inhibition cooperate to preserve tissue homeostasis and healthspan. ]]> http://www.cell-stress.com/researcharticles/2026a-parra-cell-stress/ Mon, 27 Apr 2026 10:52:02 +0000 Cell Stress https://www.cell-stress.com/?post_type=researcharticles&p=9751
Leandro Gastón Parra, Cecilia Irene Casali, Dylan Ezequiel Sendyk, Ailén Florencia Salafia, Sabrina Andrea Flor, Silvia Edith Lucangioli and María del Carmen Fernández Tome

Arachidonic acid (AA) metabolism plays a critical role in renal cell osmoadaptation. We recently demonstrated that hypertonicity induces the expression and activation of cytosolic phospholipase A2 (cPLA2). On one hand, AA released by cPLA2 enhances triacylglyceride (TG) synthesis and accumulation. On the other hand, AA is converted into prostaglandins (PG) through cyclooxygenase 2 (COX2) activity. Both processes are required for renal cell survival under osmotic stress. However, the mechanisms by which hypertonicity induces cPLA2 expression remain poorly understood. Given that we previously shown that hypertonicity regulates TG synthesis through the IRE1α-XBP1s branch of the unfolded protein response (UPR), here we examined whether XBP1s regulates the cPLA2-AA-COX2 axis in renal cells subjected to osmotic stress. We found that XBP1s modulates hypertonicity-induced expression of cPLA2 and COX2 by increasing NFκB transcriptional activity. Inhibition of IRE1α impaired normal COX2 degradation and disrupted AA metabolism, leading to a decrease in cell viability and preventing hypertonicity-induced epithelial differentiation. Prostaglandin E2 (PGE2) contributed to cell polarization facilitating adherens junction (AJ) assembly. Together, these findings highlight a central role for the IREα-XBP1s-NFκB signaling axis in coordinating cell stress responses and epithelial differentiation through AA metabolism activation. ]]> http://www.cell-stress.com/researcharticles/2026a-ebadollahibaruq-cell-stress/ Mon, 09 Mar 2026 15:04:15 +0000 Cell Stress https://www.cell-stress.com/?post_type=researcharticles&p=9745
Shima Ebadollahibaruq, Lingbin Meng and Feng Hong

Canopy homolog protein 2 (CNPY2), an endoplasmic reticulum (ER) luminal protein exhibits broad tissue distribution and regulates cellular homeostasis, including unfolded protein responses (UPR), mitochondrial dynamics, oxidative stress, and apoptosis. Beyond its role in cancer progression through pathways such as NF-κB, AKT/GSK3β, PI3K/Akt/mTOR and HIF-1α, promoting epithelial-mesenchymal transition (EMT), tumor survival and metastasis, CNPY2 is also critical in non-cancer conditions. In neurodegenerative disorders including Parkinson’s and Huntington’s, it exerts neuroprotective role by reducing oxidative stress and mitochondrial dysfunction. In cardiovascular tissues, CNPY2 leads to hypoxia-driven angiogenesis, tissue repair, and ischemia-reperfusion protection. Moreover, recent meta-analyses have linked CNPY2 downregulation with Keratoconus pathogenesis, further highlighting its tissue- specific roles. Hence, this review meticulously dissects CNPY2’s structural characteristics, expression patterns, and biological functions across cancer, cardiovascular disease, inflammation and neurological disorders, emphasizing its role on tumor initiation, microenvironmental stress, and chemoresistance, and evaluating its potential as a therapeutic target. ]]> http://www.cell-stress.com/researcharticles/2026a-carmona-gutierrez-cell-stress/ Fri, 30 Jan 2026 21:12:21 +0000 Cell Stress https://www.cell-stress.com/?post_type=researcharticles&p=9740
Didac Carmona-Gutierrez, Maria A. Bauer, Katharina Kainz¸ Martin N. Odabas and Frank Madeo

Fungal infections pose a significant global health threat with rising morbidity and mortality rates. However, the repertoire of effective antifungal drugs remains narrow, a challenge that is further exacerbated by the increasing emergence of (multi)drug-resistant strains. This underscores the urgent need for novel therapeutic strategies. Among them, antifungal peptides (AFPs) have emerged as a promising alternative. AFPs are small, naturally occurring peptides produced by a wide range of organisms, including plants, animals, fungi, and bacteria, as part of their innate immune defense. In addition, synthetic and semisynthetic variants have also been engineered. We here underscore the potential of AFPs as viable candidates for the development of next-generation antifungal therapies. In particular, we advocate their multimodal advantage that spans beyond standalone activity, including their synergistic and immune-regulatory potential. ]]> http://www.cell-stress.com/researcharticles/2026a-shen-cell-stress/ Mon, 26 Jan 2026 20:21:34 +0000 Cell Stress https://www.cell-stress.com/?post_type=researcharticles&p=9731
Zhe Shen, Hui Pan, Xiaolian Deng, Oliver Kepp, Isabelle Martins, and Guido Kroemer

Cushing syndrome (CS) is caused by an increase in endogenous or exogenous glucocorticoids, leading to major alterations in body composition, including visceral obesity, sarcopenia, osteoporosis, type 2 diabetes, and dyslipidemia. Cardiovascular complications resulting from CS are often lethal. We previously demonstrated that CS induced by oral corticosterone (CORT) supplementation in mice can be prevented by inhibition of the peptide hormone acyl-CoA binding protein (ACBP), encoded by the gene diazepam binding inhibitor (DBI). Here, we investigated whether ACBP/DBI inhibition could be used to treat, rather than prevent, CS. To this end, we initiated treatment with anti-ACBP/DBI monoclonal antibodies (mAbs) in mice three weeks after the start of CORT supplementation, when hyperphagia and body weight gain were already established. Two anti-ACBP/DBI mAbs, 7G4a (specific for mouse ACBP/DBI only) and 82 (which recognizes both mouse and human ACBP/DBI), were able to normalize food intake and halt weight gain in mice under continuous CORT treatment. In addition, both mAbs attenuated CORT-induced sarcopenia, adiposity in inguinal, perigonadal, and visceral fat depots, and fully restored metabolic parameters, including insulinemia, free fatty acids, triglycerides, and liver transaminases. In conclusion, neutralization of ACBP/DBI may serve as an effective therapeutic strategy for the treatment of established CS. ]]> http://www.cell-stress.com/researcharticles/2025a-adams-cell-stress/ Thu, 13 Nov 2025 09:01:47 +0000 Cell Stress https://www.cell-stress.com/?post_type=researcharticles&p=9707
Brittney Adams, Stanislaw Walkowiak and Mohammed K Hankir

Removing certain essential amino acids from the diet is known to promote weight loss in rodents via effects on food intake and energy expenditure. Two complementary articles by Varghese et al [Nature 643(8072)] and Lee et al [Nature Metabolism 7(6)] now show that cysteine depletion through combined dietary and genetic means in mice evokes a unique stress response in the liver to amplify these metabolic outcomes and offer a potentially new treatment option for obesity. ]]>