Lipopolysaccharide (LPS) in blood circulation causes endotoxemia and is linked to various disease conditions. Current treatments focus on preventing LPS from interacting with its receptor Toll-like receptor 4 (TLR4) and reducing inflammation. However, our body has a natural defense mechanism: reticuloendothelial cells in the liver rapidly degrade and inactivate much of the circulating LPS within minutes. But this LPS clearance mechanism is not perfect. Excessive LPS that escape this clearance mechanism cause systemic inflammatory damage through TLR4. Despite its importance, the role of reticuloendothelial cells in LPS elimination is not well-studied, especially regarding the specific cells, receptors, and mechanisms involved. This gap hampers the development of effective therapies for endotoxemia and related diseases. This review consolidates the current understanding of LPS clearance, narrates known and explores potential mechanisms, and discusses the relationship between LPS clearance and LPS signaling. It also aims to highlight key insights that can guide the development of strategies to reduce circulating LPS by way of bolstering host defense mechanisms. Ultimately, we seek to provide a foundation for future research that could lead to innovative approaches for enhancing the body’s natural ability to clear LPS and thereby lower the risk of endotoxin-related inflammatory diseases, including sepsis.

Over 50% of all patients with cancer are treated with radiotherapy. However, radiotherapy is often insufficient as a monotherapy and requires a nontoxic radiosensitizer. Squalene epoxidase (SQLE) controls cholesterol biosynthesis by converting squalene to 2,3-oxidosqualene. Given that SQLE is frequently overexpressed in human cancer, this study investigated the importance of SQLE in breast cancer and non–small cell lung cancer (NSCLC), two cancers often treated with radiotherapy. SQLE-positive IHC staining was observed in 68% of breast cancer and 56% of NSCLC specimens versus 15% and 25% in normal breast and lung tissue, respectively. Importantly, SQLE expression was an independent predictor of poor prognosis, and pharmacologic inhibition of SQLE enhanced breast and lung cancer cell radiosensitivity. In addition, SQLE inhibition enhanced sensitivity to PARP inhibition. Inhibition of SQLE interrupted homologous recombination by suppressing ataxia-telangiectasia mutated (ATM) activity via the translational upregulation of wild-type p53-induced phosphatase (WIP1), regardless of the p53 status. SQLE inhibition and subsequent squalene accumulation promoted this upregulation by triggering the endoplasmic reticulum (ER) stress response. Collectively, these results identify a novel tumor-specific radiosensitizer by revealing unrecognized cross-talk between squalene metabolites, ER stress, and the DNA damage response. Although SQLE inhibitors have been used as antifungal agents in the clinic, they have not yet been used as antitumor agents. Repurposing existing SQLE-inhibiting drugs may provide new cancer treatments. Significance: Squalene epoxidase inhibitors are novel tumor-specific radiosensitizers that promote ER stress and suppress homologous recombination, providing a new potential therapeutic approach to enhance radiotherapy efficacy.

The ongoing global health impact of SARS-CoV-2, particularly on lung and respiratory health, underscores the critical need to decipher the intricate interplay between the virus and the host innate immune system. This review provides an analysis of the key pattern recognition receptors (PRRs) involved in SARS-CoV-2 recognition within the lung, including toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs). We discuss how the engagement of these innate sentinels triggers crucial downstream consequences, ranging from protective antiviral interferon (IFN) responses to detrimental hyperinflammation characteristic of severe COVID-19. Numerous studies have identified sophisticated mechanisms employed by SARS-CoV-2 to evade or suppress early IFN induction, contributing to unchecked viral replication and subsequent immunopathology. We explore how this aberrant innate immune response drives the "cytokine storm", leading to acute respiratory distress syndrome (ARDS) and long-term sequelae. Furthermore, this review critically assesses current and emerging therapeutic strategies aimed at modulating innate immunity, including TLR agonists/antagonists, RIG-I/MDA5 modulators, NLRP3 inflammasome inhibitors, and IFN-based therapies, highlighting their potential and associated challenges. Finally, we identify key research gaps, emphasizing the need for cell-type-specific PRR studies, comprehensive mapping of viral evasion mechanisms, and the development of precision immunotherapies to enhance protective responses and mitigate pathogenic inflammation for future respiratory viral threats.

Background: Cancer emergence is associated with a series of cellular transformations that include acquired drug resistance followed by tumor metastasis. Matrix metalloproteinases (MMPs) and Hsp90 chaperone are implicated in tumor progression, however, they are not studied in the context of drug resistance.Aims: In the present study, we aimed at understanding the cross‐talk between acquired drug resistance and tumor progression, linking MMP7 and Hsp90.Methods and results: We have developed an in vitro model system for acquired drug resistance and studied the correlation between MMP7 and Hsp90. We demonstrate that enhanced drug efflux activity correlates with the induced expression and activity of MMP7, and enhanced metastatic potential of cells, however, in Hsp90‐dependent manner. The MMP7 overexpression alone could enhance the drug efflux activity marginally, and metastasis significantly. However, challenging these cells with 17AAG has significantly increased the drug efflux activity and, in contrast, decreased the metastatic potential. Evaluating our in vitro findings in mice xenografts revealed that MMP7 overexpression facilitates altered homing properties. However, these cells, in response to 17AAG treatment, exhibited increased localized tumor growth but decreased tumor metastasis.Conclusion: We demonstrated a cross‐talk between Hsp90 and MMP7 in regulating the acquired drug resistance and tumor progression. Our findings provide novel insights on targeting drug resistant‐tumors.