Immune checkpoint blockade (ICB) has demonstrated clinical efficacy in several cancers, including melanoma, lung, colorectal, and liver malignancies. However, a substantial proportion of patients fail to respond, underscoring the need for alternative immunotherapeutic strategies capable of overcoming resistance to conventional checkpoint inhibition. One such strategy involves targeting intracellular inhibitory immune checkpoints that regulate effector lymphocyte function. Rasal1, a Ras GTPase-activating protein, has been shown to negatively regulate T cell-mediated antitumor immunity. In this study, we further characterized the impact of Rasal1 impairment on tumor progression, T cell stemness, and effector function. Using an endonuclease-mediated mutation targeting the C2 domain of Rasal1, we demonstrate that Rasal1-impaired (Rasal1i) mice exhibit significantly reduced tumor growth across multiple murine cancer models. Rasal1i mice displayed increased intratumoral CD8+ T cell accumulation, activation, cytolytic capacity, and enhanced Wnt signaling. Tumor-infiltrating lymphocytes additionally exhibited increased progenitor and stem-like memory phenotypes. Notably, Rasal1 inhibition prolonged survival and potentiated aPD-1 therapy in a resistant PD-L1-expressing B16F10 melanoma model. Collectively, these findings identify Rasal1 as an intracellular inhibitory immune checkpoint that constrains T cell stemness and antitumor function, and support its further evaluation as a therapeutic target for cancer immunotherapy. ### Competing Interest Statement The authors have declared no competing interest. Canadian Institutes of Health Research, https://ror.org/01gavpb45

Regulatory T cells (Tregs) maintain immune homeostasis by suppressing excessive immune responses. In the context of cancer, Tregs are abundantly recruited to inhibit immunity against tumoral cells, facilitate immune evasion, and promote tumor progression. While Treg depletion strategies have repeatedly failed in the clinic due to severe autoimmune side effects, lack of specificity, and rapid compensatory recruitment, a critical unmet need remains for safer and more effective approaches. Emerging evidence highlights the remarkable plasticity of Tregs, allowing them to adopt an inflammatory phenotype in response to tumor-associated cytokines. Thus, leveraging this plasticity, rather than attempting broad depletion, may represent a superior anticancer strategy. This plasticity is marked by the expression of transcription factors like T-bet (Th1-like) and RORγt (Th17-like), the production of pro-inflammatory cytokines such as IFN-γ and IL-17, and even the acquisition of differential energetic preferences pertaining to glucose or glutamine. These changes can weaken Treg suppressive functions or paradoxically enhance inflammation in the tumor microenvironment, thereby creating a complex interplay between immune suppression and anti-tumor effector activity. Understanding the molecular cues driving Treg plasticity is therefore critical for designing novel therapies that shift Tregs toward an effector-like state, ultimately enhancing anti-tumor immunity and improving the efficacy of current immunotherapies. This review offers a fresh perspective on how Treg plasticity can be therapeutically harnessed to overcome the persistent limitations of conventional Treg-targeted approaches.

Mast cells (MC) play a crucial role in the tumor microenvironment (TME) by promoting tumor progression and immune evasion through the secretion of inflammatory mediators. Here, we investigate the impact of epigenetic reprogramming using a drug repurposing combination—hydralazine, a DNA methylation inhibitor, and valproate, a histone deacetylase inhibitor (HDACi)—on MC–cancer cell interactions. Human cancer cell lines (Ca Ski, MDA-MB-468, and A549) that secrete stem cell factor (SCF) were selected from a panel of tumor lines. The HMC-I MC line and the selected cancer cell lines were treated with hydralazine + valproate (HV) for 72 h, and viability assessed via trypan blue exclusion assay revealed consistent reduction across all lines. Conditioned medium (CM) from HV-treated MCs was applied to cancer cells, with MDA-MB-468 displaying resistance. CM from HV-treated cancer cells was then used to evaluate MC migration and chemotaxis, showing reduced mobility in MCs exposed to supernatants from Ca Ski and MDA-MB-468, but not A549. Flow cytometry analysis revealed that HV epigenetically suppressed the expression of pro-tumoral cytokines and MC chemoattractants, with ITAC being the only consistently upregulated cytokine. These findings demonstrate that pharmacological epigenetic reprogramming via HV modulates MC-driven tumor progression and reshapes the cytokine network, highlighting its potential as a novel immunoepigenetic therapeutic strategy in cancer.

Breast cancer (BCa) is a heterogeneous disease, initially responsive to hormone therapy but often developing resistance to both hormonal and chemotherapy treatments. Novel therapeutic strategies are needed for drug-resistant BCa. Genistein, a phytoestrogen structurally similar to estrogen, competes with estrogen for receptor binding and exhibits anti-cancer effects. In this study, we investigated the cellular and metabolic impacts of genistein, alone or in combination with chemotherapy, in two human BCa cell lines-one estrogen receptor-positive (ER+) and one estrogen receptor-negative (ER-). We observed a strong synergistic effect on cell viability at low concentrations of genistein and chemotherapy, resulting in reduced clonogenic capacity and impaired cell migration. Genistein alone modulated cellular energy metabolism, notably reducing ATP production in MCF7 (ER+) cells. This metabolic shift was linked to a decreased dependence on fatty acids for energy, coupled with a decrease in the rate-limiting mitochondrial translocase CPT1 required for fatty acid oxidation, alongside with an increase in intracellular fatty acid levels. While the most significant changes occurred in ER+ cells, ER- cells also showed responses to genistein treatment. Collectively, our findings suggest that low genistein concentrations, in combination with conventional chemotherapy, induces synergistic anti-cancer effects, promoting cellular senescence.

Obesity is a multifactorial condition characterized by excessive adiposity and systemic chronic low-grade inflammation. Recent literature reflects a growing appreciation for the complex interplay between metabolism and the immune system in the pathogenesis of obesity-related health conditions. However, this field of investigation, also known as immunometabolism, requires more in-depth study to fully understand the impact of weight loss treatments on the metabolism and function of immune cells. Despite indications that weight loss can alleviate certain metabolic dysfunctions associated with obesity, the extent to which immunometabolic parameters return to baseline posttherapy remains largely unexplored. Therefore, this review intends to re-examine critical aspects of obesity pathophysiology and highlight recent advancements in literature regarding the effects of weight loss interventions on the metabolism and function of immune cells. Addressing this field is crucial for optimizing obesity management strategies and gaining insights into long-term metabolic health outcomes.

The E2F transcription factors constitute a core transcriptional network that governs cell division and oncogenesis in multi-cellular organisms, although their molecular mechanisms remain incompletely understood. Here, we show that elevated expression of the transcription factor FOXK1 promotes transcription of E2F target genes and cellular transformation. High expression of FOXK1 in patient tumors is also strongly correlated with E2F gene expression. Mechanistically, we demonstrate that FOXK1 is O-GlcNAcylated, and loss of this modification impairs FOXK1 ability to promote cell proliferation and tumor growth. We also show that expression of FOXK1 O-GlcNAcylation-defective mutants results in reduced recruitment of the H2AK119 deubiquitinase and tumor suppressor BAP1 to E2F target genes. This event is associated with a transcriptional repressive chromatin environment and reduced cell proliferation. Our results define an essential role of FOXK1 O-GlcNAcylation in co-opting the tumor suppressor BAP1 to promote cancer cell progression through orchestration of the E2F pathway.

Small single-chain variable fragments (scFv) are promising biomolecules to inhibit and neutralize toxins and to act as antivenoms. In this work, we aimed to produce a functional scFv-6009FV in the yeast Pichia pastoris, which inhibits the pure Cn2 neurotoxin and the whole venom of Centruroides noxius. We were able to achieve yields of up to 31.6 ± 2 mg/L in flasks. Furthermore, the protein showed a structure of 6.1 % α-helix, 49.1 % β-sheet, and 44.8 % of random coil by CD. Mass spectrometry confirmed the amino acid sequence and showed no glycosylation profile for this molecule. Purified scFv-6009FV allowed us to develop anti-scFvs in rabbits, which were then used in affinity columns to purify other scFvs. Determination of its half-maximal inhibitory concentration value (IC50) was 40 % better than the scFvs produced by E. coli as a control. Finally, we found that scFv-6009FV was able to inhibit ex vivo the pure Cn2 toxin and the whole venom from C. noxius in murine rescue experiments. These results demonstrated that under the conditions assayed here, P. pastoris is suited to produce scFv-6009FV that, compared to scFvs produced by E. coli, maintains the characteristics of an antibody and neutralizes the Cn2 toxin more effectively.

Environmental risk factors possess the potential to modulate the pathogenesis of type I diabetes (T1D). Foremost among these factors are early life influences impacting the gastrointestinal (GI) tract. During infancy, both the microbiota and immune system are influenced by maternal factors contributing to key events in the neonatal GI tract. Despite the well-known importance of maternal factors on infant immune development, whether maternal immune dysregulation and dysbiosis can perpetuate the same in offspring remains largely unknown. To explore how these maternal factors impact offspring disease development, we used IgA-deficiency induced maternal dysbiosis in Non-Obese Diabetic (NOD) dams to study T1D development in their progeny. We found that maternal dysbiosis led to changes in IgA-sufficient offspring immune development resulting in heightened GI immune activity. Maternal dysbiosis also contributed to altered microbiome establishment in progeny, such that pups exhibited reduced colonic abundance of Akkermansia muciniphila and Clostridoides difficile. In adulthood, these mice exhibited a lowered incidence of T1D. This protection was replicated by fostering high incidence offspring to dysbiotic dams, prompting us to propose that altered breast milk composition in dysbiotic dams can influence immune development and microbiome establishment in offspring, contributing to T1D resistance. ### Competing Interest Statement The authors have declared no competing interest.

Adipose tissue regulates energy homeostasis and metabolic function, but its adaptability is impaired in obesity. In this study, we investigate the impact of acute PPARγ agonist treatment in obese mice and find significant transcriptional remodeling of cells in the stromal vascular fraction (SVF). Using single-cell RNA sequencing, we profile the SVF of inguinal and epididymal adipose tissue of obese mice following rosiglitazone treatment and find an induction of ribosomal factors in both progenitor and preadipocyte populations, while expression of ribosomal factors is reduced with obesity. Notably, the expression of a subset of ribosomal factors is directly regulated by PPARγ. Polysome profiling of the epididymal SVF shows that rosiglitazone promotes translational selectivity of mRNAs that encode pathways involved in adipogenesis and lipid metabolism. Inhibition of translation using a eukaryotic translation initiation factor 4A (eIF4A) inhibitor is sufficient in blocking adipogenesis. Our findings shed light on how PPARγ agonists promote adipose tissue plasticity in obesity.

Obesity and insulin resistance (IR) are global health challenges linked to metabolic diseases, such as type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). High-caloric intake, which is associated to NAFLD, induces adipocyte hypertrophy and inflammation, triggering dendritic cell (DC) activation and systemic inflammation. DC exacerbate inflammation by promoting pro-inflammatory responses, aggravating IR and NAFLD progression. NAFLD is characterized by liver fibrosis, which alters tissue stiffness that can trigger mechanosensing pathways such as the Hippo pathway in immune cell types. In this work we explored the roles of key mediators of the Hippo pathway, YAP and TAZ, in DCs within the context of liver fibrosis, obesity and IR, using a model of NAFLD induced by feeding a high fat high sucrose diet. Our findings indicate that specific deletion of YAP and/or TAZ in DCs had minimal impact on IR development and metabolic tissue inflammation. We conclude that YAP and TAZ have limited and possibly redundant roles in the immune pathophysiology of NAFLD and IR. ### Competing Interest Statement The authors have declared no competing interest. * IR : insulin resistance T2D : type 2 diabetes NAFLD : non-alcoholic fatty liver disease LTHCI : long-term high-caloric intake ER : endoplasmic reticulum DCs : dendritic cells YAP : Yes-associated protein TAZ : Transcriptional co-Activator with PDZ-binding motif TEAD : transcriptional enhanced associate domain YAPDC-KO : CD11cCre+ Yap fl/fl mice TAZDC-KO : CD11cCre+ Yaz fl/fl mice YAP/TAZDC-DKO : CD11cCre+ Yap fl/fl Taz fl/fl mice YAPDC-WT : CD11cCre− Yap fl/fl mice TAZDC-WT : CD11cCre− Yaz fl/fl mice YAP/TAZDC-WT : CD11cCre− Yap fl/fl Taz fl/fl mice HFHS : high-fat high-sucrose diet VAT : visceral adipose tissue MdM : monocyte-derived macrophages cDC1 : conventional dendritic cells type 1 cDC2 : conventional dendritic cells type 2 NCD : normal chow diet ITT : insulin tolerance test IPGTT : intraperitoneal glucose test KCs : Kupffer cells FFAs : free fatty acids IRS : insulin receptor substrate PMNs : polymorphonuclear cells AAC : area above the curve AUC : area under the curve

Gene transcription is a highly regulated process, and deregulation of transcription factors activity underlies numerous pathologies including cancer. Albeit near four decades of studies have established that the E2F pathway is a core transcriptional network that govern cell division in multi-cellular organisms1,2, the molecular mechanisms that underlie the functions of E2F transcription factors remain incompletely understood. FOXK1 and FOXK2 transcription factors have recently emerged as important regulators of cell metabolism, autophagy and cell differentiation3-6. While both FOXK1 and FOXK2 interact with the histone H2AK119ub deubiquitinase BAP1 and possess many overlapping functions in normal biology, their specific functions as well as deregulation of their transcriptional activity in cancer is less clear and sometimes contradictory7-13. Here, we show that elevated expression of FOXK1, but not FOXK2, in primary normal cells promotes transcription of E2F target genes associated with increased proliferation and delayed entry into cellular senescence. FOXK1 expressing cells are highly prone to cellular transformation revealing important oncogenic properties of FOXK1 in tumor initiation. High expression of FOXK1 in patient tumors is also highly correlated with E2F gene expression. Mechanistically, we demonstrate that FOXK1, but not FOXK2, is specifically modified by O-GlcNAcylation. FOXK1 O-GlcNAcylation is modulated during the cell cycle with the highest levels occurring during the time of E2F pathway activation at G1/S. Moreover, loss of FOXK1 O-GlcNAcylation impairs FOXK1 ability to promote cell proliferation, cellular transformation and tumor growth. Mechanistically, expression of FOXK1 O-GlcNAcylation-defective mutants results in reduced recruitment of BAP1 to gene regulatory regions. This event is associated with a concomitant increase in the levels of histone H2AK119ub and a decrease in the levels of H3K4me1, resulting in a transcriptional repressive chromatin environment. Our results define an essential role of O-GlcNAcylation in modulating the functions of FOXK1 in controlling the cell cycle of normal and cancer cells through orchestration of the E2F pathway.

Despite enormous efforts being invested in the development of novel therapies for brain malignancies, there remains a dire need for effective treatments, particularly for pediatric glioblastomas. Their poor prognosis has been attributed to the fact that conventional therapies target tumoral cells, but not glioblastoma stem cells (GSCs). GSCs are characterized by self-renewal, tumorigenicity, poor differentiation, and resistance to therapy. These characteristics represent the fundamental tools needed to recapitulate the tumor and result in a relapse. The mechanisms by which GSCs alter metabolic cues and escape elimination by immune cells are discussed in this article, along with potential strategies to harness effector immune cells against GSCs. As cellular immunotherapy is making significant advances in a variety of cancers, leveraging this underexplored reservoir may result in significant improvements in the treatment options for brain malignancies.

Acute myeloid leukemia (AML) is an aggressive hematological cancer resulting from uncontrolled proliferation of differentiation-blocked myeloid cells. Seventy percent of AML patients are currently not cured with available treatments, highlighting the need of novel therapeutic strategies. Recently, inhibition of BCL-2 with venetoclax in combination with hypomethylating agents has emerged as an attractive strategy for high-risk AML cases. Another promising target in AML is the mammalian target of rapamycin complex 1 (mTORC1) (Oki et al, Nature Comm, 2021). However, clinical inhibition of mTORC1 is limited by its reactivation through compensatory and regulatory feedback loops. To curtail these drawbacks, we adopted a strategy of inhibiting an important effector of the mTORC1 signaling pathway controlling mRNA translation - the eukaryotic initiation factor 4A (eIF4A), subunit of the translation initiation complex eIF4F. Recent evidence suggests that translational programs mediated by the mTORC1/4E-BP/eIF4F axis can support resistance to therapy in various cancer models driven by oncogenic kinases, in part by allowing cellular metabolic plasticity (Hulea L et al, Cell Metab. 2018). In fact, metabolism, and specifically mitochondrial oxidative phosphorylation, has emerged as a central dependency of AML cells, sustaining resistance to therapy and recurrence. Using the MOLM-14 human AML cell line to model therapy-resistant disease, we previously demonstrated the anti-leukemic effect of a potent and specific eIF4A inhibitor (eIF4Ai), CR-1-31-B, both in vitro and in vivo (Fooks et al, J Exp Clin Cancer Res 2022). eIF4Ai affected cellular metabolism, by reducing mitochondrial membrane potential (MMP) and the rate of ATP synthesis from mitochondrial respiration and glycolysis. Concomitantly, eIF4Ai decreased intracellular levels of specific metabolic intermediates of the tricarboxylic acid cycle (TCA cycle) and glucose metabolism, while enhancing mitochondrial ROS. Furthermore, eIF4i enhanced apoptotic priming while reducing the expression levels of the antiapoptotic factors BCL2, BCL-XL and MCL1. Importantly, CR-1-31-B acted synergistically in vitro in combination with cytarabine or venetoclax. Recently, we have expanded our characterization of the eIF4Ai/venetoclax combination in MOML-14 cells, and showed that venetoclax potentiates the CR-1-31-B-induced inhibition of cellular respiration, glycolysis and ATP production (Seahorse). The combination provokes a robust apoptotic response with different temporal dynamics to single treatment, as measured using the Incucyte platform. In vivo, we have validated the strong anti-leukemic response induced by CR-1-31-B in a MOLM-14 transplantation model, after only 7 days of treatment, and showed that venetoclax slightly potentiates this effect. In addition, eIF4A inhibition reduces the levels of several metabolic proteins (GLS1, IDH1), which supports our previous observations of decreased levels of TCA cycle metabolites. We have confirmed the metabolic and pro-apoptotic effect of eIF4Ai in a second cellular model of AML, U937. Consistent with previous results, in U937 cells CR-1-31-B induces apoptosis at low nM concentrations, reduces cellular bioenergetics, ATP production, as well as levels of pro-proliferative (cyclin D3, CDK4) and anti-apoptotic (BCL-2, MCL-1) proteins. Our collective studies highlight (i) the importance of the crosstalk between mRNA translation and metabolic regulation and (ii) that direct inhibition of translation represents an appealing therapeutic strategy for clinical cases of therapy resistance that are dependent on the mTORC1/eIF4F axis. This is of interest as several translation inhibitors are currently tested in phase 1/2 clinical trials in solid malignancies. # co-corresponding authors

Mycobacterium avium (M. avium) represents a species of concern, because of its ability to modulate the host's innate immune response, and therefore influence trajectory of adaptative immunity. Since eradicative response against mycobacteria, and M. tuberculosis/M. avium, relies on peptides actively presented on a Major Histocompatibility complex-II (MHC-II) context, we assessed paradoxical stimulation of Dendritic Cell resulting on immature immunophenotype characterized by membrane minor increase of MHC-II and CD40 despite of high expression of the pro-inflammatory tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in supernatants. Identification of M. avium leucine rich peptides forming short α-helices shutting down Type 1T helper (Th1), contribute to the understanding of immune evasion of an increasingly prevalent pathogen, and may provide a basis for future immunotherapy to infectious and non-infectious disease.

Energetic and nutritional requirements play a crucial role in shaping the immune cells that infiltrate tumor and parasite infection sites. The dynamic interaction between immune cells and the microenvironment, whether in the context of tumor or helminth infection, is essential for understanding the mechanisms of immunological polarization and developing strategies to manipulate them in order to promote a functional and efficient immune response that could aid in the treatment of these conditions. In this review, we present an overview of the immune response triggered during tumorigenesis and establishment of helminth infections, highlighting the transition to chronicity in both cases. We discuss the energetic demands of immune cells under normal conditions and in the presence of tumors and helminths. Additionally, we compare the metabolic changes that occur in the tumor microenvironment and the infection site, emphasizing the alterations that are induced to redirect the immune response, thereby promoting the survival of cancer cells or helminths. This emerging discipline provides valuable insights into disease pathogenesis. We also provide examples of novel strategies to enhance immune activity by targeting metabolic pathways that shape immune phenotypes, with the aim of achieving positive outcomes in cancer and helminth infections.

Abstract Background Acute myeloid leukemia (AML) is an aggressive hematological cancer resulting from uncontrolled proliferation of differentiation-blocked myeloid cells. Seventy percent of AML patients are currently not cured with available treatments, highlighting the need of novel therapeutic strategies. A promising target in AML is the mammalian target of rapamycin complex 1 (mTORC1). Clinical inhibition of mTORC1 is limited by its reactivation through compensatory and regulatory feedback loops. Here, we developed a strategy to curtail these drawbacks through inhibition of an mTORC1 target, the eukaryotic initiation factor 4A (eIF4A). Methods We tested the anti-leukemic effect of a potent and specific eIF4A inhibitor (eIF4Ai), CR-1-31-B, in combination with cytosine arabinoside (araC) or the BCL2 inhibitor venetoclax. We utilized the MOLM-14 human AML cell line to model chemoresistant disease both in vitro and in vivo. In eIF4Ai-treated cells, we assessed for changes in survival and apoptosis, de novo protein synthesis, targeted intracellular metabolite content, bioenergetic profile, mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP). Results eIF4i exhibits anti-leukemia activity in vivo while sparing non-malignant myeloid cells. In vitro, eIF4Ai synergizes with two therapeutic agents in AML, araC and venetoclax. eIF4Ai reduces mitochondrial membrane potential (MMP), the rate of ATP synthesis from mitochondrial respiration and glycolysis, and the expression of the antiapoptotic factors BCL2 and MCL1. Concomitantly, eIF4Ai decreases intracellular levels of specific metabolic intermediates of the tricarboxylic acid cycle (TCA cycle) and glucose metabolism, while enhancing mtROS. In vitro redox stress contributes to eIF4Ai cytotoxicity. Conclusions We discovered that AML cells rely on eIF4A-dependent cap translation for survival in vitro and in vivo. Our work indicates that eIF4A drives an intrinsic metabolic program sustaining bioenergetic and redox homeostasis. Furthermore, our work suggests that eIF4A-dependent cap translation contributes to adaptive processes involved in resistance to relevant therapeutic agents in AML.

Currently, the only available vaccine against tuberculosis is Mycobacterium bovis Bacille Calmette-Guérin (BCG). Pulmonary tuberculosis protection provided by the vaccine varies depending on the strain, the patient’s age and the evaluated population. Although the adaptive immune responses induced by different BCG strains have been widely studied, little conclusive data is available regarding innate immune responses, especially in macrophages. Here, we aimed to characterize the innate immune responses of human THP-1-derived macrophages at the transcriptional level following a challenge with either the BCG Mexico (M.BCG) or Phipps (P.BCG) strains. After a brief in vitro characterization of the bacterial strains and the innate immune responses, including nitric oxide production and cytokine profiles, we analyzed the mRNA expression patterns and performed pathway enrichment analysis using RNA microarrays. Our results showed that multiple biological processes were enriched, especially those associated with innate inflammatory and antimicrobial responses, including tumor necrosis factor (TNF)-α, type I interferon (IFN-I) and IFN-γ. However, four DEGs were identified in macrophages infected with M.BCG compared to P. BCG. These findings indicated the proinflammatory stimulation of macrophages induced by both BCG strains, at the cytokine level and in terms of gene expression, suggesting a differential expression pattern of innate immune transcripts depending on the mycobacterial strain.

Background Prostate cancer is the leading cause of cancer in men, and its incidence increases with age. Among other risk factors, pre-existing metabolic diseases have been recently linked with prostate cancer, and our current knowledge recognizes prostate cancer as a condition with important metabolic anomalies as well. In malignancies, metabolic disorders are commonly associated with aberrations in mTOR, which is the master regulator of protein synthesis and energetic homeostasis. Although there are reports demonstrating the high dependency of prostate cancer cells for lipid derivatives and even for carbohydrates, the understanding regarding amino acids, and the relationship with the mTOR pathway ultimately resulting in metabolic aberrations, is still scarce. Conclusions and perspectives In this review, we briefly provide evidence supporting prostate cancer as a metabolic disease, and discuss what is known about mTOR signaling and prostate cancer. Next, we emphasized on the amino acids glutamine, leucine, serine, glycine, sarcosine, proline and arginine, commonly related to prostate cancer, to explore the alterations in their regulatory pathways and to link them with the associated metabolic reprogramming events seen in prostate cancer. Finally, we display potential therapeutic strategies for targeting mTOR and the referred amino acids, as experimental approaches to selectively attack prostate cancer cells.

Pseudomonas aeruginosa (P. aeruginosa) is a bacterium of medical concern known for its potential to persist in diverse environments due to its metabolic capacity. Its survival ability is linked to its relatively large genome of 5.5-7 Mbp, from which several genes are employed in overcoming conventional antibiotic treatments and promoting resistance. The worldwide prevalence of antibiotic-resistant clones of P. aeruginosa necessitates novel approaches to researching their multiple resistance mechanisms, such as the use of antimicrobial peptides (AMPs). In this review, we briefly discuss the epidemiology of the resistant strains of P. aeruginosa and then describe their resistance mechanisms. Next, we explain the biology of AMPs, enlist the present database platforms that describe AMPs, and discuss their usefulness and limitations in treating P. aeruginosa strains. Finally, we present 13 AMPs with theoretical action against P. aeruginosa, all of which we evaluated in silico in this work. Our results suggest that the AMPs we evaluated have a carpet-like mode of action with a membranolytic function in Gram-positive and Gramnegative bacteria, with a clear potential of synthesis for in vitro evaluation.