The pathophysiological mechanisms of HICH have been a hot topic of research in recent years. Previous experimental studies have found a series of pathological mechanisms after the occurrence of HICH, such as inflammation, neuronal and endothelial cell apoptosis, oxidative stress (OS), etc. [17, 18]. Researchers have been trying to explore the blood mRNA spectrum of ICH. Previously, researchers used high-throughput sequencing technology to study the mRNA expression profile of patients with cerebral hemorrhage. In differentiated genes, INPP5D (inositol polyphosphatase-5-phosphatase) regulates bone marrow cell proliferation, and ITA4α (integrin) participates in white blood cell recruitment in ICH [19]. In 2019, Stamova studied the use of GeneChip HTA 2.0 arrays in patients with peripheral blood transcriptome cerebral hemorrhage. This study indicates that ICH has differentially expressed T cell receptors and CD36 genes, as well as iNOS, TLR, macrophages, and T helper pathways [20]. 250 mRNA changes (136 upregulated and 114 downregulated), regulating many ICH-related pathways in the whole blood of ICH patients, such as toll-like receptors, natural killer cells, and TGF-β [21].

However, there is limited research on the correlation between brain tissue RNA expression and peripheral blood RNA expression in patients with cerebral hemorrhage. The expression of the GSE24265 gene in brain tissue after intracerebral hemorrhage. Overexpressed genes in the surrounding area of a hematoma encode cytokines, chemokines, coagulation factors, cell growth, and proliferation factors, while low-expressed genes encode proteins related to the cell cycle or neurotrophic factors [22]. In this study, 3163 DEGs were identified in peripheral blood samples of extremely early HICH patients through RNAseq analysis. These DEGs have rich functions in various pathways such as cell death, inflammatory response, and ligand-gated ion channels [23, 24]. Previous reports have suggested that these pathways are associated with neuronal damage after cerebral hemorrhage. In addition, a total of 11 gene co-expression modules were established through WGCNA. Among them, the darkorange module is the main module related to HICH, containing 559 genes. These genes are enriched in multiple functional pathways such as the HIF-1 signaling pathway, chemokine signaling pathway, and VEGF signaling pathway. Undoubtedly, many researchers have reported that these pathways are involved in the pathogenesis of cerebral hemorrhage [25, 26]. In addition, there are reports that selective serotonin reuptake inhibitors (SSRIs) have adverse effects on the neurological prognosis of patients with cerebral hemorrhage [27]. Many genes are associated with immune system activation and other inflammatory processes [28]. It is worth mentioning that our study found that the expression of HK3, HCK, SYK, CD14, FCER1G, CYBB, and FGR increased after HICH, while the expression of SPI1 decreased, suggesting that abnormal expression of these genes may play an important role in the progression of HICH.

HK3 is mainly expressed in hematopoietic cells and tissues and is highly upregulated during the terminal differentiation process of certain acute myeloid leukemia (AML) cell line models. Here, we demonstrate that the expression of HK3 mainly originates from bone marrow cells, and the upregulation of this glycolytic enzyme is not only limited to the differentiation of leukemia cells but also occurs during the in vitro bone marrow differentiation of healthy CD34 + hematopoietic stem cells and progenitor cells. In the hematopoietic system, we found that HK3 is mainly expressed in bone marrow-derived cells. The absence of HK3 can lead to changes in chromatin structure and increase the accessibility of genes involved in cell apoptosis and stress response. HK3 promotes cell survival while also promoting glycolytic activity in AML cells, which is optional [29]. There have been no previous reports on the possible involvement of HK3 in hypertensive intracerebral hemorrhage. However, in the study by Stone JG et al., it was confirmed that HK3 can be expressed in brain tissue, and this protein can participate in cell proliferation, angiogenesis, and vascular damage [30]. Therefore, it is speculated that high expression of HK3 is likely related to cerebrovascular damage caused by hypertension, thus increasing the risk of intracerebral hemorrhage.

Hematopoietic cell kinase (HCK) is a member of the SRC cytoplasmic tyrosine kinase (SFK) family and is expressed in bone marrow and B lymphocyte lineage cells. HCK enhances the secretion of growth factors and pro-inflammatory cytokines in bone marrow cells, promotes macrophage polarization towards wound healing, and promotes alternate activation phenotypes of tumors. HCK stimulates the formation of podocytes, thereby promoting the degradation of the extracellular matrix and enhancing immune and epithelial cell invasion [31]. HCK can regulate NLRP3 and TGF-β. The signaling pathway is involved in cerebrovascular inflammation, brain cell degeneration, and apoptosis [32, 33]. Currently, no reports are confirming its association with hypertensive intracerebral hemorrhage, and the possible molecular mechanism of HCK involvement in this disease still needs further research. This study also found that HCK is an influencing factor for pulmonary infection in the HICH group. Yamada M et al. showed that bacterial pneumonia mice can secrete interferon, and HCK can regulate the Fgr/Lyn pathway to affect interferon secretion [34]; Zhang X et al. also found that HCK is highly expressed in children with sepsis, which is closely related to bacterial infection [35]. This study is consistent with the above analysis, which suggests that high expression of HCK is involved in the synthesis and secretion of pro-inflammatory factors, enhances pro-inflammatory factor activity, and thus increases the risk of pulmonary infection in hypertensive intracerebral hemorrhage.

Spleen tyrosine kinase (SYK) is a 72 kDa cytoplasmic non receptor tyrosine kinase and is a member of the SRC family. It is widely expressed in various cell types, including hematopoietic cells (such as B cells, immature T cells, neutrophils, mast cells, macrophages, and platelets) and non-hematopoietic cells (epithelial cells, fibroblasts, ACCESSED MANUSCRIPT neurons, vascular endothelial cells, liver cells, and osteoclasts), promoting various downstream signaling pathways and mediating different biological functions. Active SYK is widely involved in the transduction of various downstream signaling pathways, such as PI3K-AKT, Ras-ERK, PLC γ- NFAT, Vav1 Rac, and NF κ B pathway [36]. Liu XY et al. showed that acupuncture at Baihui and Qubin points after cerebral hematoma can alleviate neurological dysfunction, and the mechanism of action is related to the inhibition of the macroscopic inducible C-type lectin/spleen tyrosine kinase (Mincle/SYK) pathway [37]. Xie Y et al. found that inhibiting the Mincle/SYK pathway can alleviate glial inflammatory response, alleviate early vascular and neurological dysfunction in rats with subarachnoid hemorrhage, and have a positive effect on inhibiting intravascular perforation [38]. Based on the combination of this study and the above analysis, it is speculated that high expression of SYK can induce inflammatory response damage to cerebral vasculature, promote intravascular perforation, and cause cerebral hemorrhage. This study also found that high expression of SYK is a contributing factor to lung infection, and studies have found that SYK is a biomarker for lung diseases and Pseudomonas aeruginosa infection [39, 40]; There are also reports suggesting that CYK can inhibit the body's immune system and promote the replication of influenza A virus in the later stage of virus infection [41]. Therefore, the increased expression of SYK is related to both pulmonary bacterial and viral infections.

Human monocyte differentiation antigen CD14 is a pattern recognition receptor (PRR) that enhances innate immune response. In addition to its role in innate immunity, CD14 is considered to have a more general role in regulating cancer, atherosclerosis, metabolic diseases, etc. In addition, CD14 is involved in regulating insulin action and adipogenesis. FCER1G is a key molecule involved in allergic reactions, located on chromosome 1q23.3 and encoding the immunoglobulin fragment crystallization (Fc) region (Fc R) γ Subunits [42]. FCER1G is involved in many diseases, such as squamous cell carcinoma, diabetes nephropathy, multiple myeloma, and clear cell renal cell carcinoma [43]. CYBB in cDCs enhances myelin-specific CD4 + T cell activation through antigen presentation, allows CNS immune invasion, and promotes TH cell-mediated tissue damage during AT-EAE. CYBB-mediated ROS production can be detected in many hematopoietic and non-hematopoietic cell lineages, such as fibroblasts, endothelial cells, and myocardial cells. FGR mediates the induction of fibrosis by aging cells [44]. FGR kinase is associated with pro-inflammatory adipose tissue macrophage activation, diet-induced obesity, insulin resistance, and liver steatosis [45]. FGR deficiency is associated with reduced secretion of chemokines in the lungs in response to lipopolysaccharides. Girard R et al. found that CD14 belongs to the biomarker of inflammatory response, which can mediate the damage of inflammatory response to brain tissue after cerebral hemorrhage [46]. However, the mechanism by which CD14 participates in the occurrence of hypertensive cerebral hemorrhage is still unclear. Elias Oliveira J et al. pointed out that xylose oxidase-induced CD14 deficient mice had smaller lung tissue damage areas, less infiltration of neutrophils and macrophages, and milder pulmonary edema [47]. This study also found that high expression of CD14 is a risk factor for pulmonary infection in hypertensive intracerebral hemorrhage. It is speculated that high expression of CD14 is associated with more inflammatory cell infiltration and more severe pulmonary edema.

FCER1G belongs to the immunoglobulin superfamily and plays an important role in immune system defense. Fc receptors are present on the surfaces of B lymphocytes, macrophages, natural killer cells, and other cells. When these receptors are lacking, the immune function of these cells will be impaired, which can cause cellular immune disorders. Correspondingly, the expression of FCER1G can also participate in the regulation of cellular immune function. Some studies suggest that FCER1G is a key gene in renal clear cell carcinoma, and the occurrence of cancer is closely related to immune escape [48]. Some studies found that the high expression of FCER1G may induce acute cerebral infarction by promoting atherosclerosis [49]. However, there are currently no reports on the mechanism of this gene participating in hypertensive intracerebral hemorrhage both domestically and internationally, suggesting that it may be related to immune inflammatory response.

CYBB is one of the subunits of NADPH oxidase, which is an X-linked recessive inheritance. It is a common genetic factor in immune deficiency and is also related to genetic defects in phagocytes. According to previous reports, CYBB can participate in the occurrence of non-alcoholic steatohepatitis and the formation of liver tumors [50]. There is also a report confirming that CYBB can regulate the antigen processing of myelin oligodendrocytes in dendritic cells, leading to the initiation and maintenance of autoimmune neuroinflammation by brain T helper cells [44]. Additionally, CYBB gene ablation can inhibit the recruitment of T helper cells from encephalitis to central nervous cells. Although there have been no previous reports of high expression of CYBB and hypertensive intracerebral hemorrhage, it is evident that CYBB participates in neuroinflammatory damage through multiple molecular pathways.

FGR is a homolog of the oncogenic gene of the feline sarcoma virus and a member of the Scr protein tyrosine kinase family. The protein encoded by FGR is β- Two important molecules in the signaling pathway of integrin 2 can trigger negative feedback regulation of cell migration and adhesion. High expression in tumor cells can inhibit their migration and invasion activities. Gutkind JS et al. pointed out that FGR expression is related to neutrophil activation [51]. However, further research is needed on how FGR participates in the occurrence of hypertensive intracerebral hemorrhage. This study also found that FGR expression is a risk factor for lung infection. Nelson MP et al. found that knocking out FGR inhibits its tyrosine kinase activity and enhances the immune response of lung tissue to pulmonary sporidiosis [52]. Another study has confirmed that inhibiting the expression of FGR can induce alveolar macrophages to enhance their defense against atypical pneumocystis [53]. From this, it can be inferred that high expression of FGR may lead to pulmonary infection in patients with hypertensive intracerebral hemorrhage by reducing the defense effect of lung tissue against pathogenic microbial invasion.

SPI1 is a transcription factor that encodes the ETS domain and regulates gene expression during the development of myeloid cells and B lymphocytes. SPI1 is a key transcription factor after intracerebral hemorrhage, and its expression is significantly increased after intracerebral hemorrhage. In the study by Zhang G et al., SPI1 expression was significantly increased after cerebral hemorrhage [54]. SPI1 can regulate the transcriptome expression of brain microglia, enhance their phagocytosis, and is related to glycolysis, autophagy of brain cells, and myelin regeneration. Further research suggests that SPI1 may continue to participate in FCGR1, affecting central nervous system function. In this study, the expression of SPI1 in patients with hypertensive intracerebral hemorrhage significantly decreased, which is inconsistent with the above reports. It may be related to different designed primer sequences, different sample detection time points, differences in detection equipment sensitivity, and differences in patient sources. However, our research team also found that SPI1 is highly expressed in some patients with hypertensive intracerebral hemorrhage in the early stage, and gradually decreases thereafter. This suggests that SPI1 is dynamically changing during the occurrence and development of hypertensive intracerebral hemorrhage, and the reasons for this rapid and significant change are still unknown.

In this study, it was found that the expression of HK3, HCK, SYK, CD14, FCER1G, CYBB, and FGR in hypertensive intracerebral hemorrhage was higher than that in the control group, while the expression of SPI1 was lower than that in the control group. However, the above gene testing results of some patients did not conform to this trend, which may be related to differences in underlying diseases and individual health levels. However, this individual difference does not affect the progress of the study. In addition, although this study found that there may be statistical differences in the genes mentioned above between patients with epilepsy, enlarged hematoma, gastrointestinal bleeding, malnutrition, and lower limb DVT compared to those who did not, it was not found that these genes may affect adverse events, which may be due to the small sample size of the study leading to biased results.

The sample size of this study is small, and there are some errors. The innovation points of our research are difficult to summarize from the perspective of computer and contribute from the perspective of application, but there are contradictions in the contribution points of the paper, and the knowledge update iteration is fast and requires continuous learning. Early HICH data are also being updated. We will monitor the data and release the latest research results in a timely manner.