Kishor Pant

Overview Cellular metabolism is a crucial increasingly established area in cancer research, significantly influencing disease progression and supporting tumor proliferation. Genetic alterations are usually crucial in cancer biology; however, it is now evident that tumor cells undergo significant metabolic reprogramming to promote proliferation, adapt to stress, and increase metastasis [1]. Disorders like Wilson's Disease underscore the significance of metabolic equilibrium. Tumorigenesis entails intricate alterations in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, amino acid metabolism, and lipid metabolism [2,3]. Nonetheless, the mechanisms by which these processes directly promote proliferation, metastasis, and resistance to therapy remain poorly elucidated. This Research Topic, "The Role of Cell Metabolism in Development, Drug Resistance, and Survival Assessment in Cancer," includes research and reviews that explore the metabolic pathways affecting carcinogenesis, progression, drug resistance, and prognosis. Critical studies addressed the function of metabolic pathways in treatment resistance and the prospects of metabolomics for biomarker identification. The publications together enhance the understanding of metabolism's influence on cancer and highlight novel treatment possibilities. Metabolic Reprogramming: Promoting Tumor Growth Cancer cells are metabolic opportunists, modulating glucose, lipid, and amino acid pathways beyond the traditional Warburg effect. This issue's articles illustrate how reprogramming drives carcinogenesis, metastasis, and chemoresistance. Niu et al. showed that fucoxanthin, a marine carotenoid, reduces the proliferation of acute myeloid leukemia by inhibiting AKT signaling and diminishing GLUT1-mediated glucose absorption (Front Pharmacol 2025). This demonstrates how the disruption of metabolic nodes reveals therapeutic vulnerabilities. Wang et al. investigated methylglyoxal (MG), a byproduct of glycolysis with dual functions in cancer. Depending on concentration and context, MG may either promote or inhibit tumor development, indicating its therapeutic potential in controlling MG (Front Oncol 2025). A number of studies have discovered prognostic metabolic markers. Wang et al. identified a reprogramming-based signature in small cell lung cancer (SCLC), connecting MOCS2 to chemotherapy sensitivity and immunological interactions (Front Mol Biosci 2025). Jiang et al. identified a metabolic profile based on MS4A7 as a predictive factor in lung cancer. Furuhashi et al. emphasized volatile organic compounds (VOCs) as non-invasive metabolic indicators, presenting potential for diagnosis and illness monitoring. Metabolic Mechanisms and Chemoresistance Drug resistance remains to be a significant obstacle to cancer, sometimes associated with metabolic adaptability [4]. The articles underscore the necessity of identifying metabolic vulnerabilities to overcome resistance. Niu et al. revealed that inhibiting AKT-mediated glucose metabolism may re-sensitize resistant cancers. Ma et al. assessed intra-tumor heterogeneity (ITH) in prostate adenocarcinoma (PRAD), demonstrating that metabolic variety promotes treatment resistance and emphasizing MYLK2 as a potential therapeutic target. Wang et al. examined MG's dual function in resistance, highlighting that its pro-tumorigenic effects are more significant in resistant cancers (Front Mol Biosci 2025). Taken together, these studies underscore that metabolic variability and plasticity contribute to therapeutic failure, and efforts to impede these adaptations are essential for sustained treatment efficacy. Clinical Metabolomics, Biomarkers, and Personalized Therapy Clinical metabolomics, which analyzes metabolites as immediate markers of tumor physiology, has significant promise for cancer diagnosis, prognosis, and therapeutic personalization. Wang et al. established that metabolic fingerprints may forecast the prognosis of small cell lung cancer (SCLC) and characterize immunological landscapes, suggesting that resistant and susceptible tumors show unique metabolic states. Jiang et al. confirmed that MS4A7-based gene expression patterns serve as prognostic markers in lung cancer. Both studies underscore the prognostic significance of metabolomics for patient outcomes. The research of Furuhashi et al. on volatile organic compounds (VOCs) illustrates a viable non-invasive biomarker platform. VOCs, identifiable in patient biofluids, may facilitate early diagnosis, progression tracking, and real-time evaluation of therapy. The study conducted by Ma et al. further substantiates the combination of metabolomic data with genetic profiles to formulate tailored therapies aimed at addressing specific metabolic vulnerabilities. These tactics seek to optimize efficacy and reduce toxicity. Conclusions and Prospective Direction The research included in this Research Topic emphasizes cellular metabolism as a fundamental catalyst of cancer formation, progression, and treatment resistance, rather than merely an outcome of malignancy. They collectively explain how metabolic reprogramming regulates tumor development, contributes to heterogeneity, and affects treatment results, while also emphasizing the potential of clinical metabolomics and non-invasive biomarkers for prognosis and customized therapy. In near future, the integration of metabolomic data with genetic and proteomic information will be essential for identifying new metabolic hubs, enhancing treatment approaches, and addressing resistance. Improving our comprehension of the interactions among metabolism, tumor biology, and the immune response brings us nearer to novel therapies that may improve survival and quality of life for patients.

Our study reveals a novel link between primary cilia and DNA repair in cholangiocytes. We show that DNA damage response (DDR) and repair proteins localize to cilia, and deciliation impairs survival and induces S-phase arrest under genotoxic stress. Deciliated cells exhibit increased DNA damage after cisplatin, irradiation, or methyl methanesulfonate (MMS) challenge. Following irradiation, Ataxia Telangiectasia Mutated protein (ATM), p53, and p21 are downregulated in deciliated cells. Similarly, IFT88 knockout mice show heightened DNA damage, highlighting the role of primary cilia in genome stability.

Chemotherapy, radiation therapy, and surgical intervention have been the primary modalities for cancer treatment in the past few decades [1]. Although these therapies often show short-term effectiveness, they exhibit many significant drawbacks, including toxicity, a lack of specificity, and the emergence of drug resistance. The scientific community is now exploring alternative ways that could provide more specific, persistent results with reduced undesirable consequences [2].Immunotherapy is an innovative approach that has attracted significant attention and has emerged as a potent instrument in the fight against cancer [3]. The basic principle of immunotherapy is simple but effective: using the human body immune system to identify, target, and eliminate cancer and proliferating cells. This technique has the potential for sustained disease management by utilizing the immune system's inherent ability to differentiate between healthy and aberrant cells and to adapt its response over time [3].Chimeric antigen receptor (CAR)-T cell therapy has transformed targeted immunotherapy, facilitating the treatment of both haematologic and solid tumours, in addition to non-oncologic disorders [4]. This innovative therapy originated from years of progressive developments in cell-based therapeutics and continues to advance to address significant challenges. The progress in immunotherapy is highlighted in this research topic, Current Trends in Immunotherapy: From Monoclonal Antibodies to CAR-T Cells. It addresses progress from innovative cellular therapies like CAR-T cells to treatments based on monoclonal antibodies. The included articles illustrate how the future of immune-based treatments is being affected by developments in genetics, bioengineering, and molecular biology (Figure 1).A variety of investigations focus on the interactions between immune cells and cancer cells, providing new insights into how tumors evade immune identification and strategies to counteract these evasion mechanisms [5]. Others concentrate on the development of immune checkpoint inhibitors, which have revolutionised the management of malignancies such as renal cell carcinoma, non-small cell lung cancer, and melanoma. This chapter also addresses the increasing prominence of personalised vaccinations, oncolytic viruses, and bispecific antibodies [6].CAR-T cell therapy, wherein a patient's T cells are genetically modified to identify and target cancer, is among the most interesting and complex subjects addressed [7]. Initially developed for haematological malignancies, research is currently broadening its use to solid tumours, addressing challenges such as antigen heterogeneity and inhibition by the tumour microenvironment [7]. This collection of essays emphasises the progress and promise of immunotherapy as a robust and adaptable cancer treatment approach. They highlight ongoing challenges that must be addressed to fully actualise the potential of immunotherapy, including immunerelated toxicities, variability in patient responses, and the substantial expense of certain medicines.Immunotherapy is now considered a validated treatment mode. It is now strongly recognized as the fourth pillar of cancer treatment, alongside radiation, chemotherapy, and surgery [8]. Immunotherapy is expected to have increasing significance in personalized and precision oncology as research advances our understanding of the immune system and its interactions with cancer [8]. This research topic serves as a resource for researchers, physicians, and students, encapsulating a specific point in the growth of the field.

Primary cilia have been considered tumor-suppressing organelles in cholangiocarcinoma (CCA), though the mechanisms behind their protective role are not fully understood. This study investigates how the loss of primary cilia affects DNA damage response (DDR) and DNA repair processes in CCA. Human cholangiocyte cell lines were used to examine the colocalization of DNA repair proteins at the cilia and assess the impact of experimental deciliation on DNA repair pathways. Deciliation was induced using shRNA knockdown or CRISPR knockout of IFT20, IFT88, or KIF3A, followed by exposure to the genotoxic agents cisplatin, methyl methanesulfonate (MMS), or irradiation. Cell survival, cell cycle progression, and apoptosis rates were evaluated, and DNA damage was assessed using comet assays and γH2AX quantification. An in vivo liver-specific IFT88 knockout model was generated using Cre/Lox recombination. Results showed that RAD51 localized at the cilia base, while ATR, PARP1, CHK1 and CHK2 were found within the cilia. Deciliated cells displayed dysregulation in critical DNA repair. These cells also showed reduced survival and increased S-phase arrest after genotoxic challenges as compared to ciliated cells. Enhanced DNA damage was observed via increased γH2AX signals and comet assay results. An increase in γH2AX expression was also observed in our in vivo model, indicating elevated DNA damage. Additionally, key DDR proteins, such as ATM, p53, and p21, were downregulated in deciliated cells after irradiation. This study underscores the crucial role of primary cilia in regulating DNA repair and suggests that targeting cilia-related mechanisms could present a novel therapeutic approach for CCA. New and Noteworthy: Our findings reveal a novel connection between primary cilia and DNA repair in cholangiocytes. We showed that DDR and DNA repair proteins localize to cilia, and that deciliation leads to impaired cell survival and S-phase arrest under genotoxic stress. Deciliated cells exhibit heightened DNA damage, evidenced by increased γH2AX signals and comet assay results, a phenotype mirrored in in vivo IFT88 knockout mice. Furthermore, key DDR regulators, including ATM, p53, and p21, are downregulated in deciliated cells following irradiation, highlighting a crucial role for primary cilia in maintaining genome stability.

It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. We show herein that NAMPT is expressed in CCA cells, and FK866 suppresses the capacity of CCA cells to grow in a dose-dependent manner. Furthermore, by preventing NAMPT activity, FK866 significantly reduced the amount of NAD+ and adenosine 5′-triphosphate (ATP) in HuCCT1, KMCH, and EGI cells. The present study’s findings further show that FK866 causes changes in mitochondrial metabolism in CCA cells. Additionally, FK866 enhances the anticancer effects of cisplatin in vitro. Taken together, the results of the current study suggest that the NAMPT/NAD+ pathway may be a possible therapeutic target for CCA, and FK866 may be a useful medication targeting CCA in combination with cisplatin.

Cholangiocarcinoma (CCA) is a deadly form of liver cancer with limited therapeutic approaches. The pathogenesis of CCA involves the loss of primary cilia in cholangiocytes, an important organelle that regulates several key cellular functions including the regulation of cell polarity, growth, and differentiation, by a mechanism involving increased expression of deacetylases like HDAC6 and SIRT1. Therefore, cilia restoration may represent an alternative and novel therapeutic approach against CCA. Butyrate is produced by bacterial fermentation of fibers in the intestine and has been shown to inhibit SIRT1, showing antitumor effects on various cancers. Herein, we investigated the role of butyrate on CCA cell proliferation, migration, and EMT and evaluated the synergistic effects with specific HDAC6 inhibition. When CCA cells, including HuCCT1 and KMCH, were treated with butyrate, the cilia formation and acetylated-tubulin levels were increased, while no significant effects were observed in normal human cholangiocytes. Butyrate treatment also depicted reduced cell proliferation in HuCCT1 and KMCH cells, but on the other hand, it affected cell growth of the normal cholangiocytes only at high concentrations. In HuCCT1 cells, spheroid formation and cell migration were also halted by butyrate treatment. Furthermore, we found that butyrate augmented the previously described effects of HDAC6 inhibitors on CCA cell proliferation and migration by reducing the expression of CD44, cyclin D1, PCNA, Zeb1, and Vimentin. In summary, butyrate targets cancer cell growth and migration and enhances the anti-cancer effects of HDAC6 inhibitors in CCA cells, suggesting that butyrate may have therapeutic effects in CCA and other ciliopathies.

Hepatobiliary cancers comprise a wide range of malignancies such as hepatocellular carcinoma and cholangiocarcinoma, and they are some of the most challenging to treat human neoplasms. Due to the rarity of the illnesses, the development of treatment measures for malignancies of the gastrointestinal system is far behind. The number of patients eligible for curative treatment is limited due to cancer's aggressive nature and the difficulties of early identification. Furthermore, surgery is frequently intrusive and linked with a significant level of risk. The therapy result of hepatobiliary cancers is unsatisfactory due to these complicated variables, leaving significant space for improvement.

Cholangiocarcinoma (CCA) is a highly invasive and metastatic form of carcinoma with bleak prognosis due to limited therapies, frequent relapse, and chemotherapy resistance. There is an urgent need to identify the molecular regulators of CCA in order to develop novel therapeutics and advance diseases diagnosis. Many cellular proteins including histones may undergo a series of enzyme-mediated post-translational modifications including acetylation, methylation, phosphorylation, sumoylation, and crotonylation. Histone deacetylases (HDACs) play an important role in regulating epigenetic maintenance and modifications of their targets, which in turn exert critical impacts on chromatin structure, gene expression, and stability of proteins. As such, HDACs constitute a group of potential therapeutic targets for CCA. The aim of this review was to summarize the role that HDACs perform in regulating epigenetic changes, tumor development, and their potential as therapeutic targets for CCA.