Acute myeloid leukemia (AML) cells rely heavily on mitochondrial oxidative phosphorylation (OXPHOS) for energy, making mitochondrial function a promising therapeutic target. TCF12, a transcription factor belonging to the basic helix-loop-helix (bHLH) family, has been implicated in various cancers and is highly expressed in AML, where it may contribute to disease progression. However, the effects of TCF12 on AML progression and the underlying mechanisms remain unclear. This study aimed to elucidate the role of TCF12 in promoting AML cell survival and uncover the underlying mechanism. We found that TCF12 was highly expressed in AML and was associated with poor patient prognosis. Knockdown of TCF12 significantly inhibited AML cell growth, suppressed glycolysis, increased ROS accumulation, and induced mitochondrial dysfunction. Additionally, TCF12 was shown to promote EZH2 transcription, whereas its knockdown increased TXNIP expression, thereby inhibiting AML progression. In summary, TCF12 promotes AML progression by regulating EZH2-mediated suppression of TXNIP, thereby enhancing glycolysis, maintaining mitochondrial function, regulating ROS levels, and promoting cell survival, which underscores its potential as a therapeutic target.
Emerging evidence links reactive oxygen species modulator 1 (ROMO1), a key mitochondrial ROS regulator, to rheumatoid arthritis (RA) pathogenesis. However, its exact mechanism remains elusive given the conflicting evidence about its specific function. We used a four-level integrative framework combining multi-omics data and literature‑supported mechanistic inference. At the genetic level, Mendelian randomization (MR) was performed to explore potential causal relationships between ROMO1, IL2RA, HLA-DR, MIF, and RA risk, followed by differential expression analysis and machine learning-based feature selection to identify key mROS genes. The temporal expression dynamics of ROMO1 were assessed in RA progression. At the cellular and tissue levels, we integrated single-cell RNA sequencing and spatial transcriptomics to map cell-type-specific expression and synovial localization of ROMO1-related immune cells and pathways. Finally, our multi-omics findings were contextualized with literature-supported mechanistic inference. (1) MR results were consistent with a potential protective effect of ROMO1 on RA (OR = 0.52) and its potential regulation of risk factors IL2RA (OR = 0.46) and HLA-DR (OR = 0.40). Conversely, IL2RA (OR = 1.42), HLA-DR (OR = 1.88), and MIF (OR = 1.17) were positively associated with RA risk. Additionally, ROMO1 was identified as a top candidate diagnostic predictor with stage-specific dynamics: downregulated in the early but upregulated in the late/remission stages. (2) Single-cell RNA sequencing showed ROMO1's cell-specific expression in CD14+ HLA-DR+ CD74+ monocytes and CD4+ IL2RA+ T cells. Cell communication analysis further suggested that these cells may participate in MIF pathway regulation. Spatial transcriptomics subsequently identified that ROMO1-related cells localized to synovial pathological regions, with MIF pathway changes correlated with RA progression. (3) Finally, literature-supported mechanistic inference suggests that ROMO1 may modulate mROS levels to promote anti-inflammatory M2 macrophage polarization, which could theoretically contribute to reduced systemic inflammation and the alleviation of multi-organ decline in RA. This integrated multi-omics investigation, supported by literature-based mechanistic inference, suggests ROMO1 as a stage-dependent biomarker candidate and potential immune regulator in RA.
Characterized by renal inflammation and structural damage, lupus nephritis (LN) is a severe and often debilitating complication of systemic lupus erythematosus. The dynamic regulation of RNA processing, stability, and translation by N6-methyladenosine (m6A) modification has been implicated in the pathophysiology of LN. As an m6A reader, insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) plays a crucial role in the pathogenesis of various kidney diseases, yet its precise function in LN remains unclear. IGF2BP2 expression was measured in kidney specimens from LN patients and MRL/LPR mice. MRL/lpr mice were administered IGF2BP2 short hairpin RNA adeno-associated viral vectors, followed by evaluation of proteinuria, renal function, and histology. In vitro experiments employed lipopolysaccharide (LPS) stimulation of human kidney tubular epithelial cells (HK-2) to simulate LN inflammatory responses and further investigated the mechanism of IGF2BP2. Molecular interactions were validated via RNA immunoprecipitation and luciferase reporter assays. IGF2BP2 expression is significantly upregulated in LN and positively correlated with proinflammatory factor levels. Knockdown of IGF2BP2 significantly improved renal injury and alleviated renal inflammatory responses in MRL/LPR mice, as well as reduced LPS-induced inflammatory responses in HK-2 cells. Mechanistically, under LN pathological conditions, IGF2BP2 recognized m6A modifications on signal transducer and activator of transcription 1 (STAT1) mRNA and enhanced its stability, leading to the activation of proinflammatory signaling, exacerbation of renal inflammation, and ultimately renal injury. The m6A reader IGF2BP2 promotes proinflammatory signaling in LN by recognizing m6A-modified STAT1 mRNA. Targeting the IGF2BP2-STAT1 axis may represent a potential therapeutic strategy to ameliorate renal inflammatory responses in LN.
Tc17 cells and Tc17.1 cells contribute synovial inflammation during the development of rheumatoid arthritis (RA). However, the modulatory mechanisms of synovial Tc17 cells and Tc17.1 cells remain elusive. In the current study, we performed transcriptome profiling analysis on sorted live synovial Tc17 cells and Tc17.1 cells from a mouse model of collagen-induced arthritis (CIA). We found an array of differentially expressed genes (DEGs), which might be involved in the metabolism, cytokine signaling, and other biological aspects in synovial Tc17 and Tc17.1 cells. Importantly, we identified zinc finger protein 24 (ZNF24), a transcription factor, among the DEGs. ZNF24 knockdown impaired Tc17 differentiation and function in vitro, as evidenced by lower expression of IL-17A, RORγt, GM-CSF, IL-22, perforin, and granzyme B. ZNF24 knockdown resulted in similar effects on Tc17.1 differentiation and function in vitro. Furthermore, ZNF24 knockdown weakened the effects of Tc17 cells and Tc17.1 cells on inducing pro-inflammatory mediator expression in synovial fibroblasts. Adoptive transfer of Tc17.1 cells significantly exacerbated CIA development, whereas ZNF24-knockdown ameliorated the detrimental effect of Tc17.1 cells. Synovial fibroblasts up-regulated ZNF24 expression in Tc17 and Tc17.1 cells in a direct contact manner. The expression pattern and effect of ZNF24 were also observed in patients with RA and human Tc17 cells and Tc17.1 cells. Taken together, our study suggests that ZNF24 is a positive regulatory factor for Tc17 and Tc17.1 cells to exert pro-inflammatory effects in RA. We thus unveiled a novel mechanism by which the functions of synovial Tc17 cells and Tc17.1 cells are modulated.
Diffuse alveolar hemorrhage (DAH) is a lethal, female-biased complication of systemic lupus erythematosus (SLE). While adaptive immunity is a known driver, the role of innate lymphoid cells (ILCs) in DAH and the contribution of sex hormones to this process remain unclear. To characterize pulmonary ILC remodeling during DAH and evaluate whether androgen signaling modulates natural killer (NK) cell homeostasis and disease severity. A pristane-induced DAH model was established in C57BL/6J and Rag2 -/- mice. Pulmonary ILCs were profiled by single-cell transcriptomics and flow cytometry. Baseline sex differences were compared between healthy humans and mice. In vivo interventions included male castration, female testosterone propionate (TP) administration, and antibody-mediated NK cell depletion. DAH was accompanied by a marked reduction in pulmonary NK cell frequency in both C57BL/6J and Rag2 -/- mice, indicating an innate feature independent of adaptive lymphocytes. DAH-associated NK cells displayed an activated but constrained state, showing increased expression of effector-associated genes Prf1 and Ifng, together with the inhibitory receptor gene Lag3. At baseline, healthy human females and female mice exhibited lower NK cell frequencies than males. While male castration did not significantly alter DAH severity, TP administration in females restored pulmonary NK cell dominance and significantly attenuated disease severity. NK cell depletion prior to challenge led to a trend toward more severe hemorrhage (p = 0.084). Pulmonary NK cells are reduced in a lupus-associated DAH model and may participate in disease development. Androgen treatment restores pulmonary NK cell predominance and attenuates DAH severity, supporting further investigation of strategies aimed at restoring or preserving pulmonary NK cell homeostasis and function as potential therapeutic approaches for DAH.
