PMX-53

Microplastic is an emerging environmental pollutant with potential health risks. Recent studies have shown that microplastic could impair gut homeostasis in mammals. Although it has been widely demonstrated that gut dyshomeostasis could impact renal health through the gut-kidney axis, the effects of microplastic-induced gut dyshomeostasis on renal health and underlying mechanisms are still largely unknown. In the current work, we found that polystyrene microplastics (PS-MPs) treatment impaired the gut barrier, increased urinary complement-activated product C5a levels and renal C5aR expression, leading to chronic kidney disease-related symptoms in mice. Restoring the gut barrier using an antibiotic mixture effectively alleviated PS-MPs-induced kidney injury, indicating the involvement of the gut-kidney axis in PS-MPs-induced renal injury. Moreover, it also mitigated PS-MPs-induced alterations in urinary C5a levels and renal C5aR expression, suggesting that the renal C5a/C5aR pathway might be involved in PS-MPs' impacts on the gut-kidney axis. Further experiments using a C5aR inhibitor, PMX53, verified the vital role of renal C5a/C5aR pathway activation in the development of kidney injury induced by PS-MPs. Collectively, our results suggest that PS-MPs induce kidney injury in mice by impairing the gut barrier, increasing C5a levels, and ultimately activating the renal C5a/C5aR pathway, highlighting the crucial role of the gut-kidney axis in PS-MPs-induced kidney injury.

High-grade serous ovarian cancer (HGSC), with a modest response to immune checkpoint blockade (ICB) targeting PD-1/PD-L1 monotherapy, is densely infiltrated by M2-polarized tumor-associated macrophages (TAMs) and regulatory T (Treg) cells. The complement C5a/C5aR1 axis contributes to the programming of the immunosuppressive phenotype of TAMs in solid tumors and represents a promising immunomodulatory target for treating HGSCs. Here, we aimed to identify the relevance of C5aR1 in prognosis, immune microenvironment, and immunotherapy response in HGSCs. The expression and relationship of C5aR1 with tumor-infiltrating immune cells were assessed by immunohistochemistry and flow cytometry in the training cohort (n = 120) and fresh HGSC tissues (n = 36). Transcriptomic analyses of the xenografts delineated the mechanisms driving the immunomodulatory activity of PMX53, an orally bioavailable C5aR1 inhibitor. Therapeutic relevance was confirmed in ex vivo tumor cultures and The Cancer Genome Atlas (TCGA) datasets. C5aR1 expression independently predicted dismal prognosis and was linked to the immunoevasive subtype of HGSC, characterized by increased infiltration of pro-tumor cells (Treg cells, M2-polarized macrophages, and neutrophils) and impaired CD8⁺T functions. PMX53 antagonized subcutaneous tumor growth, modulated immunosuppressive mechanisms and synergized with aPD-1 in several tumor types. Single-cell RNA-seq analysis revealed predominant C5aR1 expression in TAMs, with an immunosuppressive-related expression signature in C5aR1⁺TAMs. Furthermore, the combination of C5aR1 and PD-L1 was associated with specific molecular characteristics and matched clinical response annotations. Therefore, the abundance of C5aR1 could predict an inferior prognosis in HGSCs, and incorporating PD-L1 may serve as a novel predictive biomarker to guide therapeutic options.