e21531 Background: Melanoma immunotherapy faces challenges due to heterogeneous patient responses. Current predictive biomarkers are not available in clinical practice. Serum lipids, crucial in tumor biology, show prognostic potential but lack consistent validation. To develop and validate a machine learning (ML) prognostic model integrating systemic lipid metabolism factors for predicting overall survival in melanoma patients receiving immunotherapy. Methods: A retrospective study of 381 melanoma patients was conducted. LASSO and Cox regression analyses identified prognostic features. Eight ML algorithms were trained and validated on a 7:3 split dataset to build the model. The best model was deployed as a publicly accessible application. We conducted SHAP analysis at 1-year, 3-year, and 5-year survival timepoints to generate variable importance rankings for each time node. To further investigate the key populations benefiting from the protective factor and explore whether this protection might be mediated through lipid regulation, we performed subgroup and interaction analyses using previously established thresholds. Results: The LASSO-Cox model demonstrated superior performance. Multivariable analysis identified mucosal subtype, advanced AJCC stage, high Lactate Dehydrogenase, and Ki67 index as risk factors, while high high-density lipoprotein cholesterol (HDL-C) was a protective factor. SHAP analysis ranked HDL-C as the most important predictive feature. Subgroup analysis revealed a more pronounced protective effect of high HDL-C in patients with hyperlipidemia. Finally, the model was deployed as a web (https://melanomaslnmodel.shinyapps.io/Shiny/) application to facilitate its potential clinical utility. Conclusions: HDL-C is a significant prognostic factor in melanoma immunotherapy. The web-based model provides an accurate risk prediction tool, highlighting the importance of monitoring lipid profiles in patient management.

The prognosis of advanced melanoma remains poor, and immune checkpoint inhibitor monotherapy often shows limited efficacy, especially in acral and mucosal subtypes. This challenge is particularly relevant for Chinese patients. We conducted this retrospective cohort study to evaluate outcomes associated with the addition of anlotinib to anti-PD-1 plus IFN-α1b as first-line treatment for advanced melanoma. A total of 211 patients with stage Ⅲ-IV unresectable melanoma treated between June 2020 and June 2024 were included, of whom 179 received the doublet and 32 received the triplet therapy. Propensity score overlap weighting was applied to substantially improve the balance of measured baseline characteristics between the two groups. After weighting, triplet therapy was associated with longer overall survival than doublet therapy, with a median overall survival of 35.8 versus 16.2 months, respectively (HR, 0.42; 95

Melanoma is the most life-threatening skin cancer with increasing incidence around the world. Although recent advances in targeted therapy and immunotherapy have brought revolutionary progress of the treatment outcome, the survival of patients with advanced melanoma remains unoptimistic, and metastatic melanoma is still an incurable disease. Therefore, to further understand the mechanism underlying melanoma pathogenesis could be helpful for developing novel therapeutic strategy. A20 is a crucial ubiquitin-editing enzyme implicated immunity regulation, inflammatory responses and cancer pathogenesis. Herein, we report that A20 played an oncogenic role in melanoma. We first found that the expression of A20 was significantly up-regulated in melanoma cell lines. Then, we showed that knockdown of A20 suppressed melanoma cell proliferation in vitro and melanoma growth in vivo through the regulation of cell-cycle progression. Moreover, A20 could potentiate the invasive and migratory capacities of melanoma cell in vitro and melanoma metastasis in vivo by promoting epithelial-mesenchymal transition (EMT). Mechanistically, we found that Akt activation mediated the oncogenic effect of A20 on melanoma development, with the involvement of glycolysis. What's more, the up-regulation of A20 conferred the acquired resistance to Vemurafenib in BRAF-mutant melanoma. Taken together, we demonstrated that up-regulated A20 promoted melanoma progression via the activation of Akt pathway, and that A20 could be exploited as a potential therapeutic target for melanoma treatment.

Background: Risk factors for sentinel lymph node (SLN) metastasis in melanoma have been studied. However, there remains a lack of widely applicable models with considerable predictive potential for clinical use. Objective: To developed a well-performing machine learning-based model for predicting SLN metastasis in melanoma patients. Methods: This study collected data on 351 melanoma patients with sentinel lymph node biopsy from our center. Univariate and multivariate logistic regression was used for recognizing key features. The optimal model was selected from 10 machine learning algorithms based on the F1 score. SHapley Additive exPlanations was employed to interpret the outcome of the predictive model. R package Shiny was used to develop a web tool. Results: The neural network model was chosen with the highest F1-score (0.73), indicating considerable predictive accuracy and calibration. SHapley Additive exPlanations results indicate the related factors for SLN metastasis in melanoma patients were Breslow thickness, microsatellites, Ki67 index, and subtype. Ultimately, we developed a web-based tool to promote the clinical application of the model. Limitations: Retrospective study, single institution. Conclusions: This study established a robust and interpretable machine learning approach for melanoma SLN metastasis prediction. With high sensitivity and accuracy, this approach could reduce misdiagnosis rates and alleviate patient suffering.

The pathogenesis of cancer is complicated, with metabolic reprogramming and angiogenesis as the hallmark characteristics. Recent reports have unveiled that the glycolytic metabolite lactate could modify histone lactylation to epigenetically regulate gene expressions and biological processes in cancer, while the effect on tumor angiogenesis remains elusive. By taking advantage of melanoma as the model, we first proved that lactate and histone lactylation facilitated melanoma angiogenesis both in vitro and in vivo. Then, through RNA-sequencing and a series of biochemical assays, we found that lactate promoted the transcription of suppression of tumorigenicity 2 (ST2) in tumor-associated endothelial cells via the enhancement of histone lactylation at its promoter, so that to increase the response of endothelial cells to pro-angiogenic interleukin-33 (IL-33) stimulation. In addition, lactate could also suppress high endothelial venules transition of endothelial cells, which was critical for tumor development. Ultimately, the effect of anti-angiogenic drug synergized with lactate dehydrogenase (LDH) inhibition/ST2 inhibition on melanoma growth was proved in vivo. Taken together, we demonstrated that lactate-mediated histone lactylation promotes melanoma angiogenesis via IL-33/ST2 axis, which delineated a novel regulatory relationship among lactate, histone lactylation and angiogenesis in cancer, and provided a promising combined therapeutic strategy to target angiogenesis from the perspective of cell metabolism and epigenetics in cancer.

Besides the important pathogenic mechanisms of melanoma, including BRAF-driven and immunosuppressive microenvironment, genomic instability and abnormal DNA double-strand breaks (DSB) repair are significant driving forces for its occurrence and development. This suggests investigating novel therapeutic strategies from the synthetic lethality perspective. Poly (ADP-ribose) polymerase 4 (PARP4) is known to be a member of the PARP protein family. The low expression of PARP4 is significantly associated with defective DSB repair markers and poor prognosis in melanoma. Further research revealed that PARP4 plays a role in DSB repair by regulating the non-homologous end joining (NHEJ) pathway through its involvement in Ku80 mono-ADP-ribosylation. Moreover, from a synthetic lethality perspective, PARP4 expression is associated with ATM inhibitor sensitivity. Overall, our study provides new and valuable insights into the function of PARP4 and melanoma pathogenesis and suggests that ATM inhibitor may be a promising therapeutic approach for treating melanoma with low PARP4 expression.

Excessive salt intake is a widespread health issue observed in almost every country around the world. A high salt diet (HSD) has a strong correlation with numerous diseases, including hypertension, chronic kidney disease, and autoimmune disorders. However, the mechanisms underlying HSD-promotion of inflammation and exacerbation of these diseases are not fully understood. In this study, we observed that HSD consumption reduced the abundance of the gut microbial metabolite L-fucose, leading to a more substantial inflammatory response in mice. A HSD led to increased peritonitis incidence in mice, as evidenced by the increased accumulation of inflammatory cells and elevated levels of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and monocyte chemotactic protein-1 (MCP-1, also known as C-C motif chemokine ligand 2 or CCL2), in peritoneal lavage fluid. Following the administration of broad-spectrum antibiotics, HSD-induced inflammation was abolished, indicating that the proinflammatory effects of HSD were not due to the direct effect of sodium, but rather to HSD-induced alterations in the composition of the gut microbiota. By using untargeted metabolomics techniques, we determined that the levels of the gut microbial metabolite L-fucose were reduced by a HSD. Moreover, the administration of L-fucose or fucoidan, a compound derived from brown that is rich in L-fucose, normalized the level of inflammation in mice following HSD induction. In addition, both L-fucose and fucoidan inhibited LPS-induced macrophage activation in vitro. In summary, our research showed that reduced L-fucose levels in the gut contributed to HSD-exacerbated acute inflammation in mice; these results indicate that L-fucose and fucoidan could interfere with HSD-promotion of the inflammatory response.

Age-related hearing loss (ARHL) is the most common sensory disorder associated with human aging. Chronic inflammation is supposed to be an important contributor to ARHL. Yet, the underlying mechanisms of developing cochlear inflammation are still not well understood. In this study, we found that the inflammation, endoplasmic reticulum (ER) stress and necroptosis signalings are activated in the cochlea of aged C57BL/6 mice. ER stress activator tunicamycin (TM) induced necroptosis in cochlear HEI-OC1 cells and cochlear explants, while necroptosis inhibitors protected cochlear cells from ER stress-induced cell death. The antioxidants inhibited necroptosis and protected HEI-OC1 cells from TM insults. Necroptotic HEI-OC1 cells promoted the activation of the co-cultured macrophages via Myd88 signaling. Moreover, necroptosis inhibitor protected from TM-induced hearing loss, and inhibited inflammation in C57BL/6 mice. These findings suggest that ER stress-induced necroptosis promotes cochlear inflammation and hearing loss. Targeting necroptosis serves as a potential approach for the treatment of cochlear inflammation and ARHL.

BackgroundInterferon-alpha1b (IFN-α1b) has shown remarkable therapeutic potential as adjuvant therapy for melanoma. This study aimed to develop five machine learning models to evaluate the efficacy of postoperative IFN-α1b in patients with advanced melanoma.MethodsWe retrospectively analyzed 113 patients with the American Joint Committee on Cancer (AJCC) stage III-IV melanoma who received postoperative IFN-α1b therapy between July 2009 and February 2024. Recurrence-free survival (RFS) and overall survival (OS) were assessed using Kaplan-Meier analysis. Five machine learning models (Decision Tree, Cox Proportional Hazards, Random Forest, Support Vector Machine, and LASSO regression) were developed and compared for their capacity to predict the outcomes of patients. Model performance was evaluated using concordance index (C-index), time-dependent receiver operating characteristic (ROC) curves, and decision curve analysis.ResultsThe 1-year, 2-year, and 3-year RFS rates were 71.10%, 43.10%, and 31.10%, respectively. For OS, the 1-year, 2-year, and 3-year OS rates were 99.10%, 82.30%, and 75.00%, respectively. The Decision Tree (DT) model demonstrated superior predictive performance with the highest C-index of 0.792. Time-dependent ROC analysis for predicting 1-, 2-, and 3-year RFS based on the DT model is 0.77, 0.79 and 0.76, respectively. Serum albumin emerged as the important predictor of RFS.ConclusionsOur study demonstrates the considerable efficacy DT model for predicting the efficacy of adjuvant IFN-α1b in patients with advanced melanoma. Serum albumin was identified as a key predictive factor of the treatment efficacy.

The low objective response of immune checkpoint inhibitors (ICIs) remains a great challenge in advanced melanoma therapy. Interferon-alpha has been proven to be a promising combination regimen with ICI in a phase Ib/II trial. Herein, we evaluated the efficacy and safety of interferon-alpha 1b plus PD-1 monoantibody in a real-world Chinese metastatic melanoma cohort. Profiles of patients diagnosed with unresectable stage IV (AJCC 8th Edition) between December 1st, 2018 and February 28th, 2022 from the Department of Dermatology, Xijing Hospital were reviewed. All of them received the combination treatment of interferon-alpha 1b (600 μg every other day) plus PD-1 monoantibody (Pembrolizumab 2 mg/kg or Toripalimab 240 mg or Sintilimab 200 mg, every 3 weeks) for at least 12 weeks. The efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST V1.1). The safety data were identified according to Common Terminology Criteria for Adverse Events (CTC AE) V.5.0. In total, 70 patients were included. 50

Supplementary figures, tables and figure legends

Supplementary Figure from Integrative Genomic Profiling Uncovers Therapeutic Targets of Acral Melanoma in Asian Populations

AbstractPurpose: Acral melanoma is the major subtype of melanoma seen in Asian patients with melanoma and is featured by its insidious onset and poor prognosis. The genomic study that elucidates driving mutational events is fundamental to the development of gene-targeted therapy. However, research on genomic profiles of acral melanoma in Asian patients is still sparse. Experimental Design: We carried out whole-exome sequencing (WES) on 60 acral melanoma lesions (with 55 primary samples involved), targeted deep sequencing in a validation cohort of 48 cases, RNA sequencing in 37 acral melanoma samples (all from the 60 undergoing WES), and FISH in 233 acral melanoma specimens (54 of the 60 undergoing WES included). All the specimens were derived from Asian populations. Results: BRAF, NRAS, and KIT were discerned as significantly mutated genes (SMG) in acral melanoma. The detected COSMIC signature 3 related to DNA damage repair, along with the high genomic instability score, implied corresponding pathogenesis of acral melanoma. Moreover, the copy number gains of EP300 were associated with the response of acral melanoma to targeted therapy of A485 (a p300 inhibitor) and immune checkpoint blockade treatment. In addition, the temporal order in mutational processes of the samples was reconstructed, and copy-number alterations were identified as early mutational events. Conclusions: Our study provided a detailed view of genomic instability, potential therapeutic targets, and intratumoral heterogeneity of acral melanoma, which might fuel the development of personalized strategies for treating acral melanoma in Asian populations.

Melanoma is the most lethal skin cancer that originates from epidermal melanocytes. Recently, long non-coding RNAs (lncRNAs) are emerging as critical regulators of cancer pathogenesis and potential therapeutic targets. However, the expression profile of lncRNAs and their role in melanoma progression have not been thoroughly investigated. Herein, we firstly obtained the expression profile of lncRNAs in primary melanomas using microarray analysis and unveiled the differentially-expressed lncRNAs compared with nevus. Subsequently, a series of bioinformatics analysis showed the great involvement of dysregulated lncRNAs in melanoma biology and immune response. Further, we identified lncRNA CD27-AS1-208 as a novel nuclear-localized factor with prominent facilitative role in melanoma cell proliferation, invasion and migration. Mechanistically, CD27-AS1-208 could directly interact with STAT3 and contribute to melanoma progression in a STAT3-dependent manner. Ultimately, the role of CD27-AS1-208 in melanoma progression in vivo was also investigated. Collectively, the present study offers us a new horizon to better understand the role of lncRNAs in melanoma pathogenesis and demonstrates that CD27-AS1-208 up-regulation contributes to melanoma progression by activating STAT3 pathway. Targeting CD27-AS1-208 in melanoma cells can be exploited as a potential therapeutic approach that needs forward validation in clinical trials in the future.

Objective: Capsaicin (CPS) is a major component of the red pepper, and its anti-tumor property has been confirmed. However, the underlying mechanism of this anti-tumor effect has not been fully clarified, so we conducted this study to evaluate the role of mitochondrial fission and subsequent mitochondrial dysfunction in CPS-induced apoptosis of melanoma cells. Methods: Two melanoma cell lines and melanocytes were treated with CPS alone or in combination with ruthenium red (a transient receptor potential vanilloid 1 [TRPV] antagonist), Z-VAD-FMK (a pan-caspase inhibitor), or N-acetyl-L-cysteine (an antioxidant). Cell vitality was tested using a cell counting kit-8 assay. The expression levels of related proteins were examined by Western blotting. Apoptosis, intracellular reactive oxygen species, mitochondrial membrane potential, adenosine triphosphate levels, and mitochondrial dynamics were analyzed by flow cytometry, luminometry, and confocal laser microscopy, respectively, and compared between groups. Results: CPS treatment significantly inhibited the vitality of melanoma cells (For A2058 cells: 0 vs. 120 μmol/L: [100.00% ± 0%] vs. [51.02% ± 6.40%], P < 0.05; For WM35 cells: 0 vs. 120 μmol/L: [100.00% ± 0%] vs. [51.80% ± 3.45%], P < 0.05) but exerted less impact on normal melanocytes. CPS promoted melanoma cell apoptosis through TRPV channels and the caspase cascade. CPS treatment then led to TRPV channel-dependent mitochondrial dysfunction with an increase in reactive oxygen species generation (For A2058 cells: CPS vs. CPS+RR: [2.34 ± 0.30] vs. [1.34 ± 0.12], P < 0.05; For WM35 cells: CPS vs. CPS+RR: [2.25 ± 0.25] vs. [1.65 ± 0.13], P < 0.05), dissipation of the mitochondrial membrane potential (Control vs. CPS: [1.00 ± 0] vs. [0.61 ± 0.08], P < 0.05), and adenosine triphosphate reduction ( P < 0.05). In addition, reactive oxygen species generation contributed to CPS-induced melanoma cell apoptosis. Mitochondrial fission was subsequently proved to connect CPS treatment to mitochondrial dysfunction, which was also TRPV channel-dependent, thereby inducing melanoma cell apoptosis. Conclusion: Our study highlights the role of mitochondrial fission and its related mitochondrial dysfunction in mediating the pro-apoptotic effect of CPS in melanoma. These findings deepen our understanding of the mechanisms underlying the anti-tumor activity of CPS and indicate the clinical relevancy of extending the use of this agent for cancer therapy.

We previously reported that cytoprotective Heme oxygenase-1, HO-1 (HMOX1) gene-modified human placenta-derived mesenchymal stem cell (HO-1-PMSC) improved placental vascularization in vitro. In the current study, we explored the protective benefit of HO-1-PMSC transplantation in a preeclampsia (PE)-like rat model. A model of PE was successfully constructed by intraperitoneal injection of N-nitro-L-arginine methyl ester (L-NAME). Blood pressure and urinary protein levels were measured. Doppler ultrasound was examined to understand uteroplacental perfusion. ELISA was used to examine the serum levels of VEGF, PlGF, sFlt-1, and sEng. The placentas and fetuses were weighed to verify the improvement in pregnancy outcome. Immunohistochemical and H&E staining was used to detect microvessel density (MVD) in placental tissues and kidney pathology, respectively. The distribution of GFP-labeled PMSC in the placenta were observed under fluorescence microscopy. Blood pressure and proteinuria were reduced and kidney damage was improved. PE rat models treated with PMSC and HO-1-PMSC exhibited an increase in the quality of fetuses and placentas, MVD, VEGF, and PlGF expression, but substantially decreased expression of sFlt-1 and sEng. Doppler ultrasound showed that the placental perfusion was improved. Green fluorescent tracing experiments verified that the cells were successfully transplanted into the placenta and distributed in the blood vessels, indicating that the cells might participate in the process of angiogenesis. These results indicate that therapy with HO-1-PMSC could improve placental vascular dysplasia, increase placental perfusion, control PE symptoms, and promote pregnancy outcome by regulating the balance of angiogenic and antiangiogenic factors or directly participating in the repair of placental vessels in a PE-like rat model.

Introduction: Preeclampsia is characterized by overactive inflammation at the uteroplacental interface, leading to trophoblasts dysfunction. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) is a crucial glycolytic regulator which has recently been found to participate in the pathological inflammatory states. This study aimed to investigate the role of PFKFB3 in the inflammation-induced damage in tmphoblasts, and elucidate the underlying mechanisms. Methods: Immunohistochemistry, qRT-PCR, and Western blot analysis (WB) were used to detect the expression of PFKFB3 in preeclamptic and normal placentas. Lipopolysaccharide (LPS)-induced HTR8/SVneo cells were established as the in vitro model to simulate the overactive inflammation at the uteroplacental interface of PE, which were subsequently transfected with PFKFB3 siRNA. The expression of PFKFB3, NF-kappa B-p-p65, phosphorylation states of NF-kappa B-p-p65, ICAM-1, Bcl-2, BAX, and MMP2 were detected by WB. qRT-PCR was used to detect the expression of TNF-alpha and IL-1 beta. The ICAM-1 expression was also reflected by monocyte adhesion assay. Reactive Oxygen Species (ROS) levels were detected by DCFH-DA (2,7-Dichlorodi-hydrofluorescein diacetate). Apoptosis was detected using Annexin V-FITC staining. Migration and invasion were measured by wound-healing and transwell assays. Results: PFKFB3 was up-regulated in the preeclamptic placenta. In LPS-treated HTR-8/Svneo cells, the inhibition of PFKFB3 blocked the NF-kappa B signal pathway, thereby downregulating the expression of proinflammatory cytokines and adhesion molecules, meanwhile, PFKFB3 knockdown significantly alleviated monocyte adhesion, oxidative stress, apoptosis, and reinstated migration and invasive capacity. Discussion: PFKFB3 controls the LPS-induced inflammation via the NF-kappa B pathway and impacts trophoblasts function such as adhesion, oxidative stress, apoptosis, migration, and invasion, thereby potentially participating in the preeclamptic etiopathogenesis.

Recombinant human interferon-α1b (IFN-α1b) is the first genetic engineered drug of China and is approved for cancer treatment by Chinese Food and Drug Administration. Although recombinant IFN-α1b is biologically and therapeutically active, its long-term efficacy against advanced melanoma is unknown. Ninety patients who were diagnosed with stage IV melanoma and received recombinant IFN-α1b therapy in our department were included in this study. The safety and efficacy of IFN-α1b were analyzed. IFN-α1b was overall well tolerated, with only 7.8% of the patients showing grade 3 toxicity and none with grade 4 toxicity or treatment-related death. The most common adverse effect was fever (78.9%). Furthermore, increasing the drug dosage showed no increase in the incidence of adverse events. The median overall survival (mOS) of the cohort was 14.1 months (95% confidence interval, 11.3-16.9 months). There was no significant difference of the mOS between samples of various primary sites. In the 42 patients who had not received prior adjuvant interferon therapy, the objective response rate, disease control rate and clinical benefit rate were 7.1, 28.5 and 21.4%, respectively. Our findings suggest that systemic IFN-α1b treatment is a relatively safe therapy and could prolong the survival of patients with unresectable metastatic melanoma.

INTRODUCTION:Abnormal placental vascular development is a possible cause of preeclampsia. Mesenchymal stem cell (MSC)-based therapy is a promising approach for tissue repair and angiogenesis. Further, heme oxygenase-1 (HO-1) has beneficial effects on the angiogenic balance during pregnancy. We explored the effects of HO-1 overexpression on placental vascularization using human placenta-derived MSCs (hPMSCs).METHODS:hPMSCs were isolated from term placenta, and the HO-1 gene was transfected with a lentivirus. Proliferation, migration, and apoptosis of hPMSCs and HO-hPMSCs were examined using CCK8 assay, trans-well assay, and flow cytometry, respectively. Paracrine secretion of the angiogenesis factors VEGF and PlGF, as well as the anti-angiogenesis factors sFlt-1 and sEng, from hPMSC/HO-hPMSCs was measured by qRT-PCR and ELISA. Human umbilical cord endothelial cells and a villus-decidua co-culture were treated with conditioned media to study the effect of HO-1-hPMSCs on tube formation and villus vascular remodeling.RESULTS:HO-1 significantly improved the proliferation and migration of hPMSCs. Additionally, HO-1 reduced hPMSCs apoptosis. The levels of VEGF were increased in HO-1-hPMSCs, whereas those of sFlt-1 decreased. Tube formation assays showed that the conditioned media from HO-1-hPMSCs resulted in more branching points than those from the controls. The villus-decidua co-culture system confirmed that HO-1-hPMSCs are conducive to angiogenesis and vascular remodeling.DISCUSSION:HO-1-modified hPMSCs improve placental vascularization by promoting a balance of pro- and anti- angiogenesis factors, which is worthy of further study as an alternative treatment for preeclampsia.

Abstract Purpose: Enhanced lipogenesis and mitochondrial function are two critical metabolic characteristics in melanoma, but their crosstalk involved in tumor biology and targeted therapy remains unknown. ATP-citrate lyase (ACLY) is a crucial lipogenic enzyme that is greatly implicated in tumor development, but its role in mitochondrial function and melanoma pathogenesis has not been elucidated. Experimental Design: In vitro and in vivo functional experiments were performed to determine the effect of ACLY on melanoma growth. mRNA expression profile analysis and a panel of biochemical assays were used to investigate the role of ACLY in mitochondrial oxidative phosphorylation and the underlying mechanism. The effect of combined ACLY inhibition on the efficacy of MAPK inhibition therapy was also examined. Results: We first found that ACLY expression was increased in melanoma and facilitated cell proliferation and tumor growth both in vitro and in vivo. Subsequent mRNA expression profile analysis and functional studies unveiled that ACLY specifically activated MITF–PGC1α axis to promote mitochondrial biogenesis and melanoma growth. Mechanistically, ACLY enhanced the activity of acetyltransferase P300, increasing the histone acetylation at MITF locus to promote MITF–PGC1α axis transcription. More importantly, the combined inhibition of ACLY sensitized BRAF-mutant melanoma to MAPK inhibition by suppressing MITF–PGC1α axis. Conclusions: We demonstrate that ACLY epigenetically potentiates oxidative phosphorylation to promote melanoma growth and MAPK inhibition adaptive resistance. Our study discovers the novel crosstalk between lipogenesis and mitochondrial function in tumor biology and highlights targeting ACLY as a potent therapeutic approach via simultaneously impairing tumor growth and MAPK inhibition resistance in melanoma.