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DHCR24<sup>+</sup> tumor epithelial cells drive cisplatin resistance in bladder cancer by enhancing cholesterol metabolism to activate lipid raft-associated MAPK signaling
Oncogene, Published online: 29 August 2026; doi:10.1038/s41388-026-03967-7
DHCR24+ tumor epithelial cells drive cisplatin resistance in bladder cancer by enhancing cholesterol metabolism to activate lipid raft-associated MAPK signalingComplete biosynthesis of the anticancer cephalotaxinone and homoerythratine
GLP1-E2 therapy delays autoimmune diabetes in late-stage prediabetic NOD mice and potentiates low-dose anti-CD3 therapy for enhanced disease protection
Diabetologia. 2026 May 18. doi: 10.1007/s00125-026-06750-1. Online ahead of print.
ABSTRACT
AIMS/HYPOTHESIS: Anti-CD3 monoclonal antibody (aCD3) delays progression to stage 3 type 1 diabetes in high-risk individuals by modulating autoimmune activity. Nevertheless, responses remain variable and transient, with therapy providing only indirect beta cell protection. We investigated whether glucagon-like peptide-1-17Γ-oestradiol conjugate (GLP1-E2), a beta cell-targeted fusion compound that enhances beta cell survival and function, could potentiate a short low-dose aCD3 course in preventing autoimmune diabetes in NOD mice. We hypothesised that co-targeting immune dysregulation and beta cell fragility would provide complementary and potentially synergistic benefits, resulting in more durable protection than either monotherapy.
METHODS: Female late-stage prediabetic NOD mice were randomised into four groups: untreated controls, aCD3 monotherapy, GLP1-E2 monotherapy and combination therapy. aCD3 was administered intravenously at 2.5 Β΅g/day for 5 consecutive days, while GLP1-E2 was given subcutaneously at 100 nmol kg-1 day-1 for 18 weeks. Mice were monitored longitudinally for diabetes onset. The pancreas was analysed by spatial transcriptomics and immunostaining to assess immune infiltration, beta cell integrity and molecular pathway alterations.
RESULTS: At 30 weeks of age, diabetes incidence was 77% in untreated controls, 66% in mono aCD3-treated mice and 61% in mono GLP1-E2-treated mice. Combination therapy significantly reduced diabetes incidence to 38% (pβ€0.001) and delayed disease onset by 6 weeks, with sustained protection persisting for 5 weeks after treatment cessation. GLP1-E2 monotherapy reduced islet immune cell infiltration to a similar extent as aCD3 mono- and combination therapy, without affecting peripheral lymphocyte counts. Spatial transcriptomics showed increased gene responses linked to beta cell stress (Hspa5, Eif2ak3, Xbp1, Ddit3), dedifferentiation (Cd81), 'disallowed' genes (Oat, Igfbp4), antigen presentation (H2-K1, H2-Q6, H2-Ab1, H2-Eb1) and inflammation (Cxcl10, Cxcl9, Ccl5) during disease progression. These processes were attenuated by mono- and combination therapy, with aCD3 mostly restoring beta cell identity and GLP1-E2 reducing beta cell stress and immunogenicity. Staining for CD81 and TUNEL in 17-week-old treated mice revealed levels comparable to 12-week-old normoglycaemic NOD mice, while being increased in 17-week-old untreated mice. This reduced beta cell dedifferentiation and death was associated with improved beta cell protection and better preservation of beta cell mass at 26.5 weeks compared with new-onset (diabetic) mice.
CONCLUSIONS/INTERPRETATION: Low-dose aCD3 or GLP1-E2 monotherapy delayed diabetes onset and preserved beta cell mass in female NOD mice, while the combination provided substantially superior protection. Simultaneously targeting immune dysregulation and beta cell vulnerability highlights the potential of combination therapy to enhance and prolong immunotherapeutic efficacy in type 1 diabetes.
PMID:42149241 | DOI:10.1007/s00125-026-06750-1
Integrated proteomics and metabolomics analysis reveals mechanisms by which SFYC decoction regulates airway inflammation in asthma
J Ethnopharmacol. 2026 Mar 30;365:121612. doi: 10.1016/j.jep.2026.121612. Online ahead of print.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Airway inflammation is one of the primary pathological characteristics of asthma. Soufeng Yuchuan (SFYC) decoction, a compound formula derived from multiple traditional Chinese medicine prescriptions, is widely applied clinically and exhibits significant therapeutic efficacy against asthma. However, its anti-asthmatic mechanisms remain incompletely understood.
MATERIALS AND METHODS: Asthmatic rat models induced by ovalbumin (OVA) and ferroptosis models induced by erastin in BEAS-2B cells were established. Proteomics and metabolomics analyses were conducted on lung tissues and serum. Key ferroptosis-related targets (GPX4, SLC7A11/SLC3A2, GCLC, GSS, and VDAC2) were validated using Western blotting, RT-qPCR, and biochemical assays. The direct anti-ferroptosis effects of SFYC-containing serum were compared with ferrostatin-1 and blank serum in vitro.
RESULTS: Integrated omics analysis revealed that ferroptosis, glutathione metabolism, and ROS signaling pathways were the core targets modulated by SFYC. In vivo, SFYC significantly reduced airway inflammation and ROS accumulation, restored pulmonary GSH levels, upregulated the expression of GPX4, GCLC, GSS, SLC7A11, and SLC3A2, and downregulated VDAC2 expression (P < 0.05). In vitro, SFYC-containing serum effectively reversed erastin-induced lipid peroxidation, iron overload, GSH depletion, ROS elevation, and apoptosis in BEAS-2B cells, demonstrating comparable or superior efficacy to ferrostatin-1.
CONCLUSION: SFYC alleviates airway inflammation in asthma primarily by inhibiting ferroptosis. This study provides evidence that SFYC exerts anti-asthmatic effects, at least in part, via the regulation of ferroptosis pathways.
PMID:41921764 | DOI:10.1016/j.jep.2026.121612