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The development of chemoresistance is a major challenge in the treatment of several types of cancers in clinical settings. Stemness and chemoresistance are the chief causes of poor clinical outcomes. In this context, we hypothesized that understanding the signaling pathways responsible for chemoresistance in cancers is crucial for the development of novel targeted therapies to overcome drug resistance. Among the aberrantly activated pathways, the PI3K-Akt/Wnt/β-catenin signaling pathway is clinically implicated in malignancies such as colorectal cancer (CRC) and glioblastoma multiforme (GBM). Aberrant dysregulation of phospholipase D (PLD) has been implicated in several malignancies, and oncogenic activation of this pathway facilitates tumor proliferation, stemness, and chemoresistance. Crosstalk involving the PLD and Wnt/β-catenin pathways promotes the progression of CRC and GBM and reduces the sensitivity of cancer cells to standard therapies. Notably, both pathways are tightly regulated and connected at multiple levels by upstream and downstream effectors. Thus, gaining deeper insights into the interactions between these pathways would help researchers discover unique therapeutic targets for the management of drug-resistant cancers. Here, we review the molecular mechanisms by which PLD signaling stimulates stemness and chemoresistance in CRC and GBM. Thus, the current review aims to address the importance of PLD as a central player coordinating cross-talk between the PI3K/Akt and Wnt/β-catenin pathways and proposes the possibility of targeting these pathways to improve cancer therapy and overcome drug resistance. PLD Signaling in Cancer: Unveiling Pathways to Overcome Chemoresistance Cancer coming back after it seemed to have gone away is a big problem in treating cancers like colorectal cancer and a brain cancer called glioblastoma multiforme. This research looks at the part played by cancer stem cells (CSCs - cells within a tumor that can self-renew and cause the cancer to grow and come back) in cancer coming back and not responding to treatment. The scientists found that a pathway in the cells, called the Wnt/β-catenin signaling pathway, is important for keeping CSCs going. They also found that an enzyme (a type of protein that speeds up reactions in the body) called phospholipase D1 (PLD1) helps control this pathway. By stopping PLD1, they could lower the ability of CSCs to keep renewing themselves and make them more responsive to chemotherapy. This means that focusing on PLD1 could be a new way to treat cancers that don’t respond to existing treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

The tumor microenvironment (TME) is a complex ecosystem composed of not only malignant cells but also diverse stromal and immune cell populations that collectively shape tumor behavior. Metabolism is a central regulator of the TME, orchestrating intercellular communication through altered nutrients and signaling pathways to influence both the metabolic plasticity of cancer cells and functional balance of immune populations, ultimately determining tumor progression and antitumor immunity. Although tumor-intrinsic metabolic programs have been extensively characterized, emerging evidence highlights stromal metabolism as the dominant force sculpting immune responses within the TME. Among the nonmalignant stromal constituents, cancer-associated fibroblasts and cancer-associated adipocytes have emerged as metabolically active hubs that release and redistribute key metabolites, such as lactate, fatty acids and amino acids, to modulate the activity of both tumor and immune cells. Here we integrate recent advances in the understanding of stromal–immune metabolic crosstalk and elucidates how diverse metabolic mechanisms, including nutrient competition, mitochondrial remodeling, redox imbalance and immunometabolic rewiring, collectively reinforce an immunosuppressive TME and drive therapeutic resistance. Our study highlights the emerging strategies for selectively reprogramming these metabolic networks as potential therapeutic avenues. Deciphering these multilayered interactions will establish a conceptual and mechanistic foundation for reprogramming TME, restoring immune competence and enhancing the efficacy of current immunotherapies through metabolism-targeted interventions. stromal metabolism shapes tumor immunity and progression Cancer is not just a disease of cancerous cells but involves a complex environment around the tumor. This environment includes various cells and structures that interact with cancer cells, affecting how the cancer grows and responds to treatment. The study addresses how this environment, particularly cancer-associated fibroblasts (CAFs) and adipocytes (CAAs), influences cancer progression. Researchers found that CAFs and CAAs are not just passive structures but actively change their metabolism to support cancer growth. They conducted a review of existing studies to understand these interactions better. CAFs often increase glycolysis and produce lactate, which helps cancer cells grow. CAAs release fatty acids that fuel cancer cells and suppress immune responses. The study concludes that targeting these metabolic changes in CAFs and CAAs could improve cancer treatments by restoring immune function and reducing tumor growth. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Phospholipase D (PLD) is a potential therapeutic target against cancer. However, the contribution of PLD inhibition to the antitumor response remains unknown. We developed a potent and selective PLD1 inhibitor based on computer-aided drug design. The inhibitor enhanced apoptosis in colorectal cancer (CRC) cells but not in normal colonic cells, and in vitro cardiotoxicity was not observed. The inhibitor downregulated the Wnt/β-catenin signaling pathway and reduced the migration, invasion, and self-renewal capacity of CRC cells. In cancer, therapeutic engagement of immunogenic cell death (ICD) leads to more effective responses by eliciting the antitumor immunity of T cells. The CRC cells treated with the inhibitor showed hallmarks of ICD, including downregulation of “do not eat-me” signals (CD24, CD47, programmed cell death ligand 1 [PD-L1]), upregulation of “eat-me” signal (calreticulin), release of high-mobility group Box 1, and ATP. PLD1 inhibition subsequently enhanced the phagocytosis of cancer cells by macrophages through the surface expression of costimulatory molecules; as a result, the cancer cells were more susceptible to cytotoxic T-cell-mediated killing. Moreover, PLD1 inhibition attenuated colitis-associated CRC and orthotopically injected tumors, probably by controlling multiple pathways, including Wnt signaling, phagocytosis checkpoints, and immune signaling. Furthermore, combination therapy with a PLD1 inhibitor and an anti-PD-L1 antibody further enhanced tumor regression via immune activation in the tumor environment. Collectively, in this study, PLD1 was identified as a critical regulator of the tumor microenvironment in colorectal cancer, suggesting the potential of PLD1 inhibitors for cancer immunotherapy based on ICD and immune activation. PLD1 inhibitors may act as promising immune modulators in antitumor treatment via ICD. Colorectal cancer: Enzyme inhibition enhances immunotherapy A novel drug that can inhibit an enzyme involved in colorectal cancer progression shows promise in trials on mouse models. The phospholipase D1 (PLD1) enzyme reinforces a critical signaling pathway that promotes cancer progression and drug resistance. Using computer-aided drug design, South Korean researchers led by Do Sik Min and Gyoonhee Han at Yonsei University in Incheon and Seoul, respectively, have developed a drug that specifically binds to and inhibits PLD1. In trials, the researchers observed downregulation of PLD1’s associated signaling pathway, and reductions in the ability of colorectal cancer cells to migrate, invade and replicate. The drug suppressed the cancer cells’ “don’t-eat-me” signals and upregulated “eat-me” signals, triggering improved responses from the immune system. The drug was even more effective when used in combination with an immunotherapy agent.

Tumor cells shape the immunosuppressive tumor microenvironment (TME) through coordinated interactions with tumor-associated macrophages (TAMs), regulatory T cells (T regs ), immune checkpoint pathways and suppressive cytokines, thereby limiting the efficacy of immunotherapy across diverse cancer types. Phospholipase D (PLD) enzymes, particularly the PLD1 and PLD2 isoforms, have been implicated in oncogenic signaling and tumor progression; however, their tumor-intrinsic roles in modulating the immune landscape remain largely undefined. Here we demonstrated that both genetic ablation and pharmacological inhibition of PLD1 and PLD2 reprogram the TME and enhance antitumor immunity in a syngeneic melanoma model. Elevated PLD expression is associated with increased infiltration of M2-like TAMs, decreased ‘eat me’ signals and enhanced ‘don’t eat me’ signals. Conversely, loss or inhibition of PLD1 and PLD2 reduced T reg recruitment and enhanced infiltration of Th1, Th17 and cytotoxic CD8⁺ T cells, accompanied by downregulation of immune checkpoint molecules and restoration of T cell effector function. Depletion studies revealed that PLD-driven TAM polarization critically impairs CD8⁺ T cell-mediated antitumor responses. Mechanistically, PLD1 and PLD2 enhance CCL19 secretion, promote macrophage polarization toward an immunosuppressive phenotype and induce programmed death-ligand 1 (PD-L1) expression by activating the PI3K–Akt–NF-κB signaling axis, thereby promoting tumor immune evasion. Notably, PLD inhibition reduced CCL19 production, abrogated IFN-γ- or CCL19-induced PD-L1 expression, decreased TAM infiltration and increased CD8⁺ T cell infiltration, collectively shifting the TME toward an immune-activated state. These findings suggest that tumor-intrinsic PLD1 and PLD2 function as modulators of immune suppression and that PLD inhibition represents a promising strategy to overcome resistance to cancer immunotherapy. Targeting PLD enzymes boosts antitumor immunity in melanoma This study explores the role of phospholipase D (PLD) isoforms, PLD1 and PLD2, in melanoma, focusing on their impact on the tumor microenvironment (TME). The authors reveal that PLD1/2 are upregulated in melanoma, promoting tumor growth and immune evasion by modulating macrophage polarization and PD-L1 expression. Using CRISPR–Cas9 knockout models and pharmacological inhibition, they demonstrate that PLD1/2 deficiency shifts macrophages from an M2-like to an M1-like phenotype, enhancing T cell-mediated antitumor immunity. PLD1/2 deficiency reduces secretion of CCL19, which functions as an upstream regulator of immunosuppressive macrophage polarization and PD-L1 expression via the PI3K–Akt–NF-κB pathway. The findings suggest that targeting PLD1/2 could enhance cancer immunotherapy by reprogramming the immune landscape, highlighting the potential of PLD inhibitors as therapeutic agents. Future research could explore the applicability of these findings across different cancer types and further elucidate the signaling pathways involved. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase that plays diverse physiological roles. However, little is known about the regulation of SIRT1 activity. Here, we show that phospholipase D2 (PLD2), but not PLD1, selectively interacts with SIRT1 and increases the deacetylase activity of SIRT1. PLD2 does not interact with the other isozymes of SIRT (SIRT2–7). Two leucine residues in the LXXLL motif (L173 and L174) in the phox domain of PLD2 interact with the region essential for SIRT1 activity. PLD2 stimulates the SIRT1-mediated deacetylation of p53 independent of its lipase activity. In our study, mutagenesis of the LXXLL motif suppressed the interaction of PLD2 with SIRT1 and inhibited SIRT1-mediated p53 deacetylation and p53-induced transactivation of proapoptotic genes. Ultimately, overexpression of wild-type PLD2 but not that of LXXLL-mutant PLD2 protected cells against etoposide-induced apoptosis. Moreover, PLD2 did not protect against apoptosis induced by SIRT1 depletion under genotoxic stress. Collectively, our results suggest that PLD2 is a positive regulator of SIRT1 and modulates p53-mediated apoptosis via SIRT1. Cancer: Regulating tumor cell self-defense New details about the regulatory mechanisms that prevent tumor cell death could be exploited to increase the effectiveness of chemotherapy. The sirtuin (SIRT) protein family has been linked to both promotion and suppression of tumors in different cancers. The enzyme SIRT1 in particular deacetylates, and thereby deactivates, the key tumor-suppressing antigen p53, stopping p53 from inducing apoptosis (controlled cell death) in tumors. Do Sik Min at Yonsei University, Incheon, South Korea, and co-workers revealed that this SIRT1 deacetylation of p53 is greatly enhanced by the activity of the enzyme phospholipase D2 (PLD2). A particular region on PLD2 is required to activate SIRT1, this activation leading to protection of tumor cells from apoptosis induced by the chemotherapy drug etoposide. Therapies that target that region on PLD2 might therefore suppress a tumor’s natural resistance to chemotherapy.

Phospholipase D6 (PLD6) is a critical enzyme involved in mitochondrial fusion with a key role in spermatogenesis. However, the role of PLD6 in cancer remains unknown. Notably, Wnt signaling, energy metabolism and mitochondrial function show complex interactions in colorectal cancer (CRC) progression. Here we found that PLD6 is highly expressed in CRC and positively correlated with poor prognosis. We present a novel function of PLD6 in activating Wnt/β-catenin signaling by enhancing mitochondrial metabolism. PLD6 depletion suppresses the oncogenic properties of CRC cells and impairs mitochondrial respiration, leading to reduced mitochondrial length, membrane potential, calcium levels and reactive oxygen species. PLD6 depletion also disrupts mitochondrial metabolic reprogramming by inhibiting the tricarboxylic acid cycle and mitochondrial oxidative phosphorylation, resulting in altered intracellular levels of citrate and acetyl-CoA—both key modulators of Wnt/β-catenin activation. PLD6-mediated acetyl-CoA production enhances β-catenin stability by promoting its acetylation via the acetyltransferases CREB-binding protein and P300/CREB-binding-protein-associated factor. Consequently, PLD6 ablation reduces cancer stem cell-associated gene expression downstream of Wnt/β-catenin signaling, suppressing stem-like traits and chemoresistance to 5-fluorouracil. Furthermore, PLD6 depletion attenuates CRC tumorigenesis in both subcutaneous and orthotopic tumor models. Overall, PLD6 acts as an oncogenic switch by promoting mitochondria-mediated retrograde signaling, thereby regulating Wnt signaling in CRC. PLD6 drives Wnt signaling and cancer progression in CRC This study explores the role of a protein called phospholipase D6 (PLD6) in colorectal cancer (CRC). PLD6 is known to be involved in mitochondrial function, but its role in cancer was unclear. Researchers found that PLD6 is more active in CRC tissues compared with normal tissues, and higher levels of PLD6 are linked to worse outcomes for patients. Researchers used techniques such as CRISPR–Cas9 (a gene-editing tool) to modify PLD6 levels in cells and observed changes in cell behavior. They found that PLD6 promotes cancer cell growth, movement and survival by affecting mitochondrial metabolism and a signaling pathway called Wnt/β-catenin, which is important for cell growth and development. The study suggests that targeting PLD6 could be a potential strategy for treating CRC, as it may help reduce tumor growth and improve the effectiveness of chemotherapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Background/Objectives: Late-onset hypogonadism (LOH), characterized by declining testosterone levels with age, negatively affects the health of men, causing physical, psychological, and sexual dysfunction. Conventional testosterone replacement therapies have side effects, which has led to interest in natural alternatives. We investigated the effects of a standardized fermented Morinda citrifolia extract (FME) on oxidative stress-induced damage in TM3 Leydig and TM4 Sertoli cells. The cells were treated with H2O2 to simulate oxidative stress, followed by the FME treatment. Methods: Cytotoxicity assays, testosterone measurements, and gene and protein expression analyses were conducted to evaluate the restorative properties of FME. Results: The H2O2 treatment significantly decreased the cell viability, testosterone production, and the expression of proteins involved in testosterone synthesis and spermatogenesis, and the FME treatment improved testosterone production and restored the luteinizing hormone receptor, steroidogenic acute regulatory protein, CYP11A1, 3β-hydroxysteroid dehydrogenase, 17,20 desmolase, and 17β-hydroxysteroid dehydrogenase levels in the TM3 Leydig cells. It also reduced the expression of testosterone-degrading enzymes, aromatase and 5α-reductase. The FME treatment restored the levels of the androgen receptor and follicle-stimulating hormone receptor in the TM4 Sertoli cells. Conclusions: FME alleviates oxidative stress-induced damage in Leydig and Sertoli cells by promoting testosterone synthesis and spermatogenesis while regulating testosterone metabolism. These findings suggest that FME could be a promising candidate for the management of LOH symptoms.

Background: Previous studies have suggested that employment insecurity is associated with adverse health outcomes. We explored the association between temporary employment and smoking behaviors.Methods: We analyzed 11,795 workers (51,867 observations) from the Korea Health Panel Study (2009–2018). Employment types were categorized as regular, fixed-term, or daily, based on the duration of labor contract. The outcomes were current smoking status and changes in smoking behavior (initiation or cessation) in the following year. Generalized estimating equations were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).Results: The proportions of fixed-term and daily workers were 41.2% and 16.4% for women and 23.6% and 12.4% for men, respectively. Temporary employment was associated with increased odds of current smoking, while also demonstrating prospective associations with changes in smoking behaviors. For instance, in prospective analyses, male workers with fixed-term and daily employments were associated with a decreased likelihood of smoking cessation (OR 0.77; 95% CI, 0.65–0.91 for fixed-term employment and OR 0.66; 95% CI, 0.52–0.83 for daily employment) in the following year compared to those with regular employment. Moreover, those experiencing consecutive temporary employment was most inversely associated with smoking cessation in both men (OR 0.56; 95% CI, 0.44–0.71) and women (OR 0.37; 95% CI, 0.16–0.85) compared to those experiencing consecutive regular employment. However, no clear association between temporary employment and smoking initiation was observed in both men and women.Conclusion: Temporary employment is directly associated with current smoking and inversely associated with smoking cessation. Policies are needed to improve job insecurity among temporary employees.

Two trials enrolled a total of 2701 patients who had undergone implantation of a drug-eluting coronary stent and had been receiving dual antiplatelet therapy for at least 12 months. They were randomly assigned to either continuation or discontinuation of clopidogrel therapy. At 19.2 months after randomization, the rate of myocardial infarction or death from cardiac causes did not differ significantly between the two groups. Patients who had undergone implantation of a drug-eluting coronary stent and had been receiving dual antiplatelet therapy for at least 12 months were randomly assigned to either continuation or discontinuation of clopidogrel therapy. At 19.2 months after randomization, the rate of myocardial infarction or death from cardiac causes did not differ significantly between the two groups. Several pivotal clinical trials have shown that the use of drug-eluting coronary stents is associated with significant reductions in the risks of restenosis and need for target-lesion revascularization, as compared with use of bare-metal coronary stents. 1 On the basis of the results of these trials, drug-eluting stents have been widely used for percutaneous coronary intervention (PCI) in clinical practice. 2 However, some longer-term studies have shown that drug-eluting stents, as compared with bare-metal stents, are associated with increased rates of late stent thrombosis, death, or myocardial infarction. 3 , 4 It has been proposed that the occurrence of late clinical events may be . . .

Although brown macroalgae holds potential as an alternative feedstock, its utilization by conventional microbial platforms has been limited due to the inability to metabolize one of the principal sugars, alginate. Here, we isolate Vibrio sp. dhg, a fast-growing bacterium that can efficiently assimilate alginate. Based on systematic characterization of the genomic information of Vibrio sp. dhg, we establish a genetic toolbox for its engineering. We also demonstrate its ability to rapidly produce ethanol, 2,3-butanediol, and lycopene from brown macroalgae sugar mixture with high productivities and yields. Collectively, Vibrio sp. dhg can be used as a platform for the efficient conversion of brown macroalgae sugars into diverse value-added biochemicals. Brown macroalgae is a good candidate feedstock for biorefinery, but the major carbohydrate alginate cannot be digested by current industrial microbes. Here, the authors isolate Vibrio sp. dhg and engineer it to produce value-added biochemicals from alginate using newly developed genetic tools.