Deng M. et al. conducted a study which demonstrated that hepatocytes release high mobility group box 1 (HMGB1), which then binds to lipopolysaccharide (LPS) and is internalized into the lysosomes of macrophages and endothelial cells through the receptor for advanced glycation end-products (RAGE). Subsequently, HMGB1 causes permeabilization of the phospholipid bilayer within the acidic environment of the lysosomes. This leads to the leakage of LPS into the cytoplasm and the activation of caspase-11. Caspase-11, being an LPS receptor, plays a role in caspase-11-dependent pyroptosis, which ultimately contributes to the lethality of endotoxemia [
30,
31]. Hence, the close association between lysosomes and LPS-mediated sepsis, which can impact the pathophysiological progression of sepsis, is evident. Numerous chemicals exhibit specific affinity for lysosomal proteins, thereby governing cellular behavior [
32]. Consequently, this investigation employed RNA sequencing and bioinformatics techniques to identify four lysosome-related genes that significantly influence the prognosis of sepsis patients. These findings offer valuable insights for the development of targeted therapies aimed at lysosomal intervention.
Granulysin (GNLY) is a cytotoxic granule that is co-secreted with granzyme and perforin from the granules of human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. It has been documented to possess diverse antimicrobial properties [
33,
34]. GNLY is predominantly expressed in human CTLs and NK cells and has been implicated in a plethora of pathological conditions, including infections, cancer, transplantation, and dermatological disorders [
35]. Granzyme B (GZMB) is an integral constituent of cytolytic granules found within natural killer (NK) cells and serves as a crucial cytotoxic molecule employed by T cells to eliminate cells infected by pathogens or transformed tumor cells [
36,
37]. CD8 + T cells have the ability to induce apoptosis in target cells through the release of GZMB, which, in turn, may lead to tissue damage and restructuring [
38]. Emerging evidence indicates its involvement in the lysosome-mediated demise of the cytotoxic lymphocyte itself [
39]. Perforin (PRF1) is an essential pore-forming protein involved in lymphocyte cytotoxicity [
40]. Mutations in the PRF1 gene have been identified as a causative factor for the development of Hemophagocytic Lymphohistiocytosis (HLH) [
41]. HLH is a severe immunodeficiency and multi-organ disorder that can result in a potentially lethal hyperinflammatory state, characterized by fever, hepatosplenomegaly, and distinctive laboratory abnormalities [
42]. RAS guanyl-releasing protein 1 (RASGRP1) plays a crucial role as a guanine nucleotide exchange factor and a vital regulator of T cell receptor signaling in the immune system [
43]. In murine models, the absence of RASGRP1 leads to impaired development of T lymphocytes [
44]. In humans, deficiencies in RASGRP1 can result in a primary immunodeficiency (PID) syndrome, characterized by lymphopenia in CD4 + T cells and the development of Epstein-Barr virus (EBV)-associated B cell lymphoma [
45]. By utilizing RNA sequencing and conducting bioinformatics analysis, our study revealed that the genes GNLY, GZMB, PRF1, and RASGRP1 exhibited predominant expression within the lysosomes of T cells and NK cells. These genes were found to actively participate in crucial biological processes, including the immune system process, response to stimulus, cellular process, and signal transduction. Notably, their expression levels were significantly higher in the normal control group compared to the sepsis group. Furthermore, a positive correlation was observed between the expression of these genes and the prognosis of sepsis patients. Previous research has also indicated a strong association between these four genes and the immune response mediated by lymphocytes. Hence, it is postulated that these four genes could serve as innovative targets for precise lysosomal therapy, which plays a significant role in lysosomal-mediated inflammation and immune responses. Consequently, they may modulate the expression of lysosomal proteins, influencing the pathophysiological progression of sepsis and ultimately impacting the diverse clinical outcomes observed in patients.
In conclusion, the genes GNLY, GZMB, PRF1, and RASGRP1 exhibited significant upregulation in the normal control group and downregulation in the sepsis group, thereby displaying a positive correlation with the prognosis of sepsis patients. This observation implies that their heightened expression potentially contributes to the survival of sepsis patients. Additionally, given their association with lysosomal functions, these four genes may serve as promising targets for lysosomal therapy, thereby offering a novel avenue for the clinical management of sepsis.