bims-meract 2025-12-28 papers

Clin Transl Med. 2026 Jan;16(1): e70561

AARS1-mediated AKR1B10 lactylation stabilizes an aerobic glycolysis-positive feedback loop to drive lenvatinib resistance in hepatocellular carcinoma.

Zijian Liu, Jingsheng Yuan, Shitong Su, Jiaqi Han, Ni Zeng, Yuhan Ma, Nianyong Chen, Tao Lv.

BACKGROUND: Lenvatinib resistance (LR) represents a significant obstacle in hepatocellular carcinoma (HCC) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) is involved in tumour metabolic reprogramming; however, its role in LR remains unclear.
METHODS: Bioinformatics analyses of public databases were integrated and validated in established LR HCC cell lines. Functional assays (CCK-8, flow cytometry and Seahorse XF analysis) were performed to assess proliferation, apoptosis and aerobic glycolysis. Post-translational modifications of AKR1B10 were characterized using co-immunoprecipitation, mass spectrometry and western blot.
RESULTS: AKR1B10 was identified as a critical driver of resistance by establishing a metabolic positive feedback loop. Bioinformatics analyses and experimental validation demonstrated that AKR1B10 upregulation correlates with therapeutic resistance. Functional studies indicated that AKR1B10 promotes resistance by enhancing aerobic glycolysis. Mechanistically, alanyl-tRNA synthetase 1 mediates lactylation modification at AKR1B10 lysine 173 (K173), stabilizing AKR1B10 by blocking ubiquitin (Ub)-proteasomal degradation. Stabilized AKR1B10 interacts physically with lactate dehydrogenase A (LDHA), promoting LDHA phosphorylation at Y10 and accelerating glycolytic lactate production. The increased lactate subsequently induces histone H3K18 lactylation (H3K18la), which transcriptionally upregulates LDHA expression. Thus, a self-reinforcing AKR1B10-lactate-LDHA amplification circuit is formed. Clinical analyses confirmed elevated AKR1B10 expression in LR HCC patient tissues. Importantly, targeting this axis with the AKR1B10 inhibitor epalrestat (EPA) synergized with lenvatinib, overcoming resistance in xenograft mouse models and patient-derived xenograft models.
CONCLUSIONS: These findings establish AKR1B10 as both a biomarker and a therapeutic target in HCC. They reveal a novel lactylation-driven glycolytic adaptation mechanism and support the clinical translation of combined EPA-lenvatinib therapy.
KEY POINTS: AKR1B10 confers lenvatinib resistance by enhancing aerobic glycolysis in HCC cells. AKR1B10 undergoes AARS1-mediated lactylation at K173, stabilizing it by antagonizing ubiquitin-proteasomal degradation. AKR1B10 promotes LDHA Y10 phosphorylation, boosting lactate production, which drives H3K18la-mediated transcriptional upregulation of LDHA, creating a feed-forward loop. Targeting AKR1B10 with epalrestat synergizes with lenvatinib to overcome resistance in preclinical models.

Keywords: aerobic glycolysis; epalrestat; lactylation; lenvatinib resistance; ubiquitination

DOI: https://doi.org/10.1002/ctm2.70561

Exp Cell Res. 2025 Dec 19. pii: S0014-4827(25)00470-7. [Epub ahead of print] 114870

p38 MAPK-mediated suppression of Nrf2-MPC2 axis drives metabolic reprogramming which confers imatinib resistance in blast crisis phase of chronic myeloid leukemia.

Manish Bhat, Mythreyi Narasimhan, Ashutosh Shelar, Raghavendra Patwardhan, Santosh Kumar Sandur, Rukmini Govekar.

BACKGROUND: Metabolic reprogramming is a hallmark of cancer and its role in tumour drug resistance is emerging. This study explored its role in resistance to tyrosine kinase inhibitors (TKIs) in the blast crisis (BC) phase of chronic myeloid leukemia (CML), which occurs despite inactivation of the oncogenic Bcr-Abl by TKIs. We previously reported that this Bcr-Abl-independent resistance is mimicked in TKI-resistant CML-BC cell line and is causally associated with p38MAPK, a known modulator of metabolism. Thus, we investigated whether p38MAPK-mediated metabolic rewiring caused resistance in CML-BC.
METHODS: Imatinib sensitive and resistant CML-BC cell lines K562 and KU812 were analysed for metabolic proteins by Western blotting, metabolome by mass spectrometry, and apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) by flow cytometry. Sequence of alterations was established by inhibition and knockdown studies.
RESULTS: TKI-resistant cells exhibited enhanced glucose uptake, increased levels of GLUT1, glycolytic enzymes, and those of pyruvate and ATP which reduced upon inhibition of GLUT1, indicative of enhanced glycolysis as contributor of energy. In contrast, the cells displayed reduced NADH/NAD ratio, MMP, mitochondrial ROS which resulted in reduction in apoptotic population. Inhibition studies revealed that suppression of hyperphosphorylated p38MAPK-mediated activation of Nrf2, caused reduced mitochondrial pyruvate carrier (MPC2) expression. MPC2 inhibition in sensitive cells recapitulated the resistant phenotype with reduced MMP and ROS levels.
CONCLUSION: p38MAPK-mediated suppression of Nrf2/MPC2 axis abrogates mitochondrial function and ROS-mediated cell death while enhanced glycolysis generates ATP to sustain growth. The resultant pro-survival conditions allow leukemic cell survival under drug pressure causing resistance.

Keywords: Nrf2/MPC2 axis; chronic myeloid leukemia; imatinib resistance; metabolic reprogramming; mitochondrial dysfunction; p38MAPK signalling

DOI: https://doi.org/10.1016/j.yexcr.2025.114870

Ann Med. 2025 Dec;57(1): 2445774

Exploring the significance of fatty acid metabolism reprogramming in the pathogenesis of cancer and anticancer therapy.

Jiaao Sun, Jiahua Liu, Feng Chen, Xiaoxi Wang, Guangzhen Wu.

One of the important markers that distinguish tumor cells from normal cells is metabolic reprogramming. Among them, the reprogramming of fatty acid metabolism not only supports the fuel supply for energy but also meets the needs of rapid biosynthesis, providing selective growth advantages for tumor cells to resist harsh microenvironments. Due to the crucial role of fatty acid metabolic reprogramming in tumor metabolism, its various functions in cancer have attracted more and more attention. In this review, we summarize the mechanisms of fatty acid metabolic reprogramming in tumor cells and the series of responses (such as active ferroptosis signaling), analyze the potential impacts brought by fatty acid metabolic reprogramming in various human cancers and focus on the significance of targeting fatty acid metabolic pathways and dietary control in cancer treatment.

Keywords: Fatty acid metabolism; anticancer therapy; cancer; ferroptosis; metabolic reprogramming

DOI: https://doi.org/10.1080/07853890.2024.2445774

Cell. 2025 Dec 24. pii: S0092-8674(25)01369-8. [Epub ahead of print]

Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity.

Jian Gu, Yu Li, Qiuyang Chen, Ziyan Song, Qufei Qian, Yuan Liang, Tianning Huang, Lei Qiao, Xiangyu Li, Miao Yu, Mu Liu, Jinren Zhou, Qing Shao, Xiaozhang Xu, Robert Zeiser, Ling Lu.

Mechanisms of adaptation of regulatory T cells (Tregs) to harsh tumor metabolic microenvironments for suppression of anti-tumor immunity remain largely unclear. Here, using spatial metabolomics and transcriptomics, we show that human hepatocellular carcinoma harbored metabolically heterogeneous subregions characterized by high glutaminolysis and ammonia contents, where Tregs were frequently present but CD8+ and CD4+ effector T cells die. We found Tregs used the urea cycle to detoxify ammonia by upregulating argininosuccinate lyase (ASL); meanwhile, ammonia was also converted to spermine by the FOXP3 transcription factor regulated spermine synthase (SMS). A direct interaction between spermine and PPARγ was verified by X-ray crystallography, leading to comprehensively modulating the transcription of multiple mitochondrial complex proteins to enhance oxidative phosphorylation and immunosuppression of Tregs. Clinically, anti-PD-1-treated dying tumor cells used transdeamination to release ammonia, which reinforced Treg function, leading to immunotherapeutic resistance. Targeting ammonia production to suppress Tregs presents a potential strategy for anti-tumor immunotherapy.

Keywords: Tregs; ammonia; cancer immunotherapy; glutaminolysis; metabolic adaptation; polyamine metabolism; urea cycle

DOI: https://doi.org/10.1016/j.cell.2025.11.034