Psoriasis is a severe disease associated with the disturbance of metabolism and inflammation, but the molecular mechanisms underlying these aspects of psoriasis pathology are poorly understood. Here, we report that glutaminase 1–mediated (GLS1-mediated) glutaminolysis was aberrantly activated in patients with psoriasis and in psoriasis-like mouse models, which promoted Th17 and γδ T17 (IL-17A–producing γδ T) cell differentiation through enhancement of histone H3 acetylation of the Il17a promoter, thereby contributing to the immune imbalance and development of psoriasis. We further demonstrate that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protease was constitutively active in psoriatic CD4⁺ and γδ T cells, thereby supporting GLS1 expression by stabilizing c-Jun, which directly binds to the GLS1 promoter region. Blocking the activity of either GLS1 or MALT1 protease resolved Th17 and γδ T17 cell differentiation and epidermal hyperplasia in the psoriasis-like mouse models. Finally, IL-17A enhanced GLS1 expression via the MALT1/cJun pathway in keratinocytes, resulting in hyperproliferation of and chemokine production by keratinocytes. Our findings identify the role of the MALT1/cJun/GLS1/glutaminolysis/H3 acetylation/T17 axis in psoriasis pathogenesis and reveal potential therapeutic targets for this disease.

Emphysema is a major phenotype of chronic obstructive pulmonary disease (COPD) and reflects sustained oxidative injury and defective alveolar repair in the distal lung. While cigarette smoke is the dominant environmental trigger, endogenous epithelial programs that restrain reactive oxygen species (ROS) and preserve alveolar integrity remain poorly defined in the adult lung parenchyma. Here we identify that fat mass and obesity-associated protein (FTO) as a redox-responsive regulator in the alveolar epithelium. FTO is predominantly expressed in alveolar type II (AT2) epithelial cells and is markedly reduced in both the epithelium of human COPD patients and the lungs of cigarette smoke-exposed mice. This reduction correlated with worse pulmonary function and was inversely associated with cumulative smoking burden in human. Global attenuation of FTO expression resulted in spontaneous emphysema and impaired lung mechanics in mice. Mechanistically, FTO deficiency promotes cytochrome P450 1B1 (CYP1B1) expression via increased m⁶A modification and mRNA stabilization, thereby enhancing ROS accumulation and activating the necroptotic effector mixed lineage kinase domain-like protein (MLKL). Genetic silencing of CYP1B1 or antioxidant treatment with N-acetylcysteine (NAC) attenuated ROS and necroptosis. Moreover, conditional deletion of FTO in AT2 cells exacerbated oxidative stress, phosphorylated-MLKL/MLKL levels, and emphysematous injury in mice, indicating spontaneous emphysema driven by necroptosis—effects that were further aggravated in a chronic cigarette smoke-induced COPD model. NAC treatment effectively alleviated the COPD-related deterioration caused by FTO deficiency in AT2 cells. Together, these findings define an alveolar epithelial FTO-m⁶A-CYP1B1-ROS-MLKL axis that links redox dysregulation to necroptotic cell death and alveolar destruction, and they nominate FTO as a tractable node for redox-targeted intervention in COPD-related emphysema.

The health implications of widespread heavy metal pollution are of growing concern, particularly for respiratory diseases like Chronic Obstructive Pulmonary Disease (COPD). Preserved ratio impaired spirometry (PRISm) is an early abnormal phenotype in COPD development, yet its connection to environmental heavy metal mixtures is unestablished. Our research aimed to bridge this gap by analyzing data from 6585 U.S. adults in the 2007-2012 NHANES. Multivariable logistic regression showed elevated cadmium (Cd) increased PRISm risk (OR:1.35, 95% CI: 1.10 ∼ 1.65, P for trend < 0.05, per unit increase in log₁₀-transformed Cd, logCd). WQS (OR:1.40, 95% CI: 1.09 ∼ 1.81, per quartile increase in the mixture index of log₁₀-transformed metals), Qgcomp (OR:1.30, 95% CI: 1.05 ∼ 1.61, per quartile increase in all log₁₀-transformed metals) and BKMR (OR=1.079, 95% CI: 1.009-1.153, for increasing all log₁₀-transformed metals from the 50th to the 75th percentile) models consistently demonstrated a significant adverse effect of the metal mixture on PRISm incidence in females, with Cd identified as the primary contributor (PIP = 0.9996). A nonlinear relationship was observed for blood Cd, with a risk threshold of logCd = -0.673 (Cd = 0.510 μg/L). Mediation analysis revealed that albumin, HRR, and RAR mediated 5.06%, 3.59%, and 11.11% of the logCd-PRISm association, respectively. These findings were corroborated in two mouse models of CdCl₂ exposure (via drinking water or inhalation), which demonstrated robust lung inflammation (elevated IL-17, TNF-α, IL-13, IL-4), histopathological damage, increased EMT-related (N-cadherin, Tgf-β) and matrix degradation-related (Mmp8) mRNA expression. RNA-seq KEGG pathway analysis enriched four pathways (ECM-receptor interaction, IL-17, TNF, hematopoietic cell lineage) consistent with the phenotypic and mediation data. Collectively, these results highlight a critical role for Cd exposure in PRISm pathogenesis, warranting further prospective and mechanistic investigation.