Maintaining immune homeostasis within the liver is crucial for optimal physiological function; conversely, its disruption is intricately linked to obesity and the progression of MASLD (Petrescu et al., 2022). Recent research introduces a three-stage model: 1) recognition of hepatic stress by local immune cells and subsequent cytokine release; 2) amplification of inflammatory response by innate immune cells; and 3) tissue damage driven by adaptive immune mechanisms (3).

Although SAH has historically been attributed to hemodynamic factors, contemporary research has underscored the significant role of immune-driven inflammation in the progression of the disease. Experimental models have indicated the accumulation of immune cells, particularly T cells and monocytes/macrophages, within the vasculature, kidneys, and brain. These immune cells contribute to the increase in vascular permeability and facilitate the release of ROS, nitric oxide (NO), cytokines, and metalloproteinases, which are critical in driving vascular remodeling. Cytokines promote the formation of the neo-intima layer, reducing the lumen diameter of resistance vessels while increasing vascular stiffness and resistance (20, 22). Additionally, they affect renal tubular function by enhancing the local secretion of angiotensinogen and Ang-2, leading to sodium retention and fluid overload, ultimately elevating BP (29).

The cytokines that play a crucial role in the development of SAH are mostly pro-inflammatory, such as IL-17, TNF-α, gamma interferon (IFN-γ), and IL-1β (29, 30). Together, these cytokines lead to endothelial dysfunction, immune activation, and renal impairment, highlighting the inflammatory pathogenesis of hypertension. IL-17, mainly released by CD4⁺ and CD8⁺ T cells, triggers the expression of CCL-2 in a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent manner, which results in chronic oxidative stress and T cell infiltration in vascular smooth muscle (31). IL-6, secreted by monocytes, macrophages, and DC, polarizes CD4⁺ T cells and promotes sodium and water retention, further exacerbating SAH. TNF-α stimulates the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and NADPH oxidase, thereby enhancing the release of chemokines and adhesion molecules in blood vessels, which contributes to microvascular remodeling, sodium retention, and diminished NO production (29, 30). IFN-γ, generated by Th1 cells, is associated with angiotensinogen expression, and its deficiency has been shown to reduce renal fibrosis and increase glomerular filtration rate (32). Lastly, IL-1β, released by monocytes, T cells, and neutrophils, leads to macrophage polarization toward the pro-inflammatory M1 subtype, resulting in a substantial release of IL-6 (29, 30).

It has recently been proposed that SAH constitutes a disorder influenced by neuroinflammation (33–35), partially resulting from chronic SNS activation that stimulates microglia, which release pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6, and IFN-γ, thereby worsening high BP levels due to heightened sympathetic nerve activity. Additionally, a compromised blood-brain barrier (BBB) creates a positive feedback loop, enabling circulating inflammatory molecules, Ang-2, and gut-derived metabolites to infiltrate autonomic brain regions, exacerbating neuroinflammation and affecting autonomic regulation dysfunction (29, 36).

Overall, SAH is not merely a hemodynamic disorder, but a complex condition driven by inflammatory and neuroimmune mechanisms. Inflammation is essential in sustaining elevated BP and contributing to target organ damage. Moreover, it represents a common pathological link between MASLD and SAH, suggesting that it may be a crucial connection between these two conditions. Therefore, in the following sections, we aim to present evidence that explains how inflammation bridges MASLD and SAH, highlighting its role in their pathophysiology and potential therapeutic implications.

CXCL9 is a low-molecular-weight chemokine that belongs to the CXC chemokine family, playing a role in immunoregulatory and inflammatory processes. Its primary function is to recruit leukocytes to sites of inflammation, and it is secreted by various cell types, including T lymphocytes, NK cells, dendritic cells, macrophages, eosinophils, and non‐immune cells, such as hepatic cells (49). Additionally, it helps modulate the activation and proliferation of hepatocytes, stellate cells, and endothelial cells in the liver (Sahin, Trautwein, and Wasmuth, 2010). Semba et al. found high local expression of CXCL9 in the liver of a fatty liver mouse model with non-alcoholic steatohepatitis (50), suggesting a near correlation between steatohepatitis development and elevated local CXCL9 levels. Antibody-mediated neutralization of CXCL9 during established obesity conferred protection from hepatocellular damage (51), suggesting that activating the CXCL9 axis may represent an essential hallmark of MASLD progression. CXCL9 plays a key role in inflammation, collagen deposition, and tissue remodeling and is involved in the pathogenesis and complications of MASLD ( Figure 1A ) (52). This is demonstrated by Wang and collaborators, who found that CXCL9 was highly expressed in patients with MASH, correlating with liver injury and complications of liver disease in humans (53).

Furthermore, CXCL9 has been identified as a prognostic marker in patients with liver cirrhosis. Elevated levels of this chemokine have been reported to be associated with shorter survival in cirrhotic patients (54). Additionally, CXCL9 exacerbates the progression of MASLD by disrupting the balance between Treg/Th17 cells (55). Therefore, antagonizing this chemokine could represent a therapeutic approach to ameliorate acute and chronic fibrotic liver damage.

Contrary to expectations, some authors have reported some antifibrotic properties of CXCL9. Wasmuth and colleagues found that this chemokine exerted antifibrotic effects in vitro by suppressing collagen in mice and human liver cells (56). Similarly, Sahin and colleagues identified direct angiostatic and antifibrotic effects of the CXCR3 ligand CXCL9 in a model of experimental liver fibrosis (57). However, the observed antifibrotic and antiangiogenic effects of CXCL9 may occur through the inhibition of signaling mediated by heparan sulfate proteoglycans involves various endothelial growth factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and endothelial growth factor (EGF) ( Figure 1A ) (58).

A likely explanation for the reported elevation of CXCL9 in patients with MASLD might be positive feedback and upregulation of this protein to counteract the fibrotic milieu within damaged liver cells. However, the elevation of CXCL9 in patients with MASLD might also point to this chemokine as the initial activator of many pathways that ultimately lead to fibrosis and culminate in the development and progression of MASLD.

The function of CXCL9 in regulating BP remains not fully understood. Nevertheless, evidence indicates that the CXCL9/CXCR3 axis plays a multifaceted role in maintaining renal and vascular homeostasis (59). Research has shown that Ang 2-stimulated CXCR3-deficient mice experience elevated blood pressure due to increased AT1R levels, suggesting that the absence of CXCR3 may render them more susceptible to salt-sensitive hypertension (60). These mice display higher mortality rates and worsening interstitial fibrosis despite less pronounced inflammatory cell infiltration (61). The role of CXCR3 in fibrosis and organ damage seems paradoxical, as CXCR3 is upregulated in cases of progressive renal fibrosis ( Figure 1B ) (59). Conversely, disrupting the CXCL-9/CXCR3 pathway has been shown to improve kidney function and reduce the presence of activated macrophages and T cells in murine models, indicating a complex and context-specific function of this pathway in renal inflammation and fibrosis. Additionally, patients with SAH show elevated serum levels of CXCL9 compared to normotensive controls. Moreover, these patients presented increased counts of immunosenescent CD8+ T cells, indicating that CXCL9 could play a role in immune dysregulation and vascular inflammation in hypertension (62).

CXCL9 is a multifunctional chemokine with a central role in immune regulation, inflammation, and tissue remodeling, particularly within the liver. It is related to the pathogenesis and progression of MASLD, as it has been reported that elevated hepatic and serum levels correlate with liver injury, fibrosis, and poor prognosis. However, its role remains complex and context-dependent, as some studies report antifibrotic and angiostatic effects, possibly as a compensatory response to liver damage. Beyond the liver, the CXCL9/CXCR3 axis also appears to be involved in renal and vascular homeostasis, with implications for hypertension and systemic inflammation. While CXCL-9 is a promising biomarker and potential therapeutic target, further research is needed to clarify its dualistic roles and determine how best to modulate its activity in liver and vascular diseases.

CXCL10 is a critical chemokine secreted by many cell types, including monocytes, endothelial cells, and fibroblasts, in response to IFN-γ. The function of CXCL10 has been attributed to pleiotropic effects, including stimulation of monocytes, natural killer cells, and T-cells migration, and modulation of adhesion molecule expression. In the liver, hepatocytes are a significant source of CXCL10, which exerts and perpetuates liver inflammation, playing a crucial role in the pathogenesis of MASLD (63). However, in various types of liver injury, CXCL10 is secreted by hepatic cells in areas of lobular inflammation (64).

By binding to CXCR3, CXCL10 recruits T lymphocytes and macrophages to the liver parenchyma, promoting inflammation, apoptosis, and fibrosis (55) through the direct induction of the proinflammatory cytokine IL-9 in a liver fibrosis model (65). Additionally, a systematic review by Pan and colleagues found that CXCL10 triggers oxidative stress, fibrosis, and inflammation in MASH by activating the NF-κB pathway through activated B-cells ( Figure 1C ). This activation stimulates macrophages, leading to fibrosis and liver injury in MASLD (66).

It has been proposed that high CXCL10 levels may be involved in MASH due to the inhibition of the autophagic pathway (67). In an in vitro study, it was demonstrated that high levels of CXCL10 reduced the accumulation of phagocytic proteins and enhanced the degradation of autophagic proteins in liver cells, ultimately contributing to the onset and progression of MASH (67). Additionally, CXCL10 effects are mediated by KC, as demonstrated by the induction of inflammation in the liver and the stimulation of inflammatory monocyte infiltration, which produces CXCL10 and limits liver sinusoidal endothelial cell permeability ( Figure 1C ) (68).

Elevated CXCL10 levels also play a significant role in the pathophysiology of SAH. Antonelli and colleagues observed that patients with untreated essential hypertension showed notably higher CXCL10 serum levels than healthy individuals, suggesting that this chemokine might be involved in the pathophysiology of SAH (69). Additionally, increased Ang-2 levels are a key marker of SAH’s pathophysiology, and a close association between elevated levels of this RAS peptide and high levels of pro-inflammatory chemokines has been reported (70). In this sense, it is known that Ang-2 promotes the expression of chemokines, such as CXCL10, in various cell types, including fibroblasts, endothelial cells, and smooth muscle cells. In response, monocytes, macrophages, and T-cells migrate into the adventitia and periadventitial fat. This phenomenon is suggested to maintain vascular dysfunction, elevate oxidative stress, and lead to fibrosis, all contributing to increased BP ( Figure 1D ) (71). Campanella and collaborators found that CXCL10 can inhibit endothelial cell proliferation and, thus, prevent the endothelium regeneration needed to remove chronic alterations in the structure of blood vessels, contributing, in this manner, to perpetuate elevated systemic vascular resistance in hypertensive subjects (72). These observations support the notion that CXCL10 may function as a common mediator of immune activation and tissue injury in both hepatic and systemic settings, potentially in the inflammatory and vascular interactions that connect MASLD and SAH.

VCAM-1 is a cell surface sialoglycoprotein expressed by activated endothelial cells, tissue macrophages, DC, bone marrow fibroblasts, myoblasts, and myotubes. Its primary function consists of mediating adhesion to vascular endothelium cells and transmigration of lymphocytes, monocytes, eosinophils, and basophils into the subendothelial space during inflammation (73).

Recently, it has been associated with the onset of chronic liver diseases and fibrosis, which is upregulated and promotes MASH by mediating monocyte adhesion to the liver sinusoidal endothelial cells. In this context, VCAM-1-neutralizing monoclonal antibodies or pharmacological inhibition have provided a successful attenuation of diet-induced steatohepatitis in mouse models via reducing the proinflammatory monocyte hepatic population, which highlights the key role of VCAM-1 in the pathogenesis of chronic liver diseases ( Figure 1E ) (74). Lefere and colleagues studied endothelial dysfunction in MASLD patients, identifying VCAM-1 as an independent predictor of significant fibrosis in this population (75). Furthermore, Halima et al. investigated the interaction between VCAM-1 and liver fibrosis within the serum of patients diagnosed with chronic liver diseases. Their findings indicate that elevated levels of this molecule significantly predict unfavourable outcomes in individuals suffering from MASLD (76).

The previous results that highlight the link between VCAM-1 and MASLD can be clarified by understanding that VCAM- 1 prompts monocytes to migrate to the liver through fenestrae, possibly triggering a pro-inflammatory response, as noted by Furuta and colleagues. Their study demonstrated that lipotoxic stress in MASLD elevates VCAM-1 levels in liver sinusoidal endothelial cells due to the activation of the Mixed-Lineage Kinase 3 (MLK3) and the p38 MAPK pathway (MLK3/P38). This activation subsequently enhances the transmigration of pro-inflammatory cells, worsening the hepatic condition ( Figure 1E ). This finding is bolstered by evidence indicating that blocking VCAM-1 prevents the adhesion and migration of monocytes across the endothelium, thus hindering the progression of MASLD (74).

Toxic lipid levels caused high expression of VCAM-1, which activated HSC via the yes-associated protein-1 (YAP-1) signaling pathway. Further experiments confirmed this data, showing that the specific deletion of VCAM1 in liver endothelial cells resulted in a better liver fibrosis profile in in vitro models (77). Recently, it has been noted in a rat model that increased VCAM-1 levels in hepatic endothelium facilitate the recruitment of inflammatory macrophages, driving vascular remodeling and leading to portal tract fibrosis ( Figure 1E ) (78).

The role of VCAM-1 in developing SAH has also been studied (79, 80). Significantly higher plasma levels of VCAM-1, as part of the hypertension pathophysiology, have been previously observed in many research studies, suggesting a close interconnection (81, 82). In a rat model, Ng and his team identified a positive correlation between increased VCAM-1 levels and elevated blood pressure. They examined the expression of this chemokine in the aortic tissue of rats, discovering that those with higher blood pressure exhibited more significant levels of VCAM-1 expression (83). Evidence suggests a connection between SAH development and elevated VCAM-1 levels; however, the underlying immunopathological mechanisms remain under investigation. A proposed mechanism focuses on the chemotactic properties of VCAM-1 in the endothelium. VCAM-1 is crucial for monocyte adhesion and migration to vascular endothelium, which, in chronic inflammation as seen in SAH patients, is linked to perpetuating hypertension (79). Yin and colleagues demonstrated that inhibiting VCAM-1 with a monoclonal antibody reduces monocyte adhesion and infiltration into the endothelium, thereby protecting against arterial hypertension and dysfunction caused by Ang-2 in a mouse model (79) ( Figure 1F ). According to Palomo and colleagues, it has been suggested that chronic endothelial activation during SAH leads to a direct overexpression of VCAM-1. They initially established that sVCAM‐1 levels are elevated in hypertensive patients compared to those with normal blood pressure. They then suggested that SAH might boost the production of cell adhesion molecules, likely due to endothelial activation (84).

The data indicate that VCAM-1 is critical in MASLD and SAH due to its repetitive links to hepatic inflammation, fibrosis, vascular dysfunction, and increased BP. However, the exact role of VCAM-1 in connecting these two disorders is still uncertain. It remains unclear whether VCAM-1 expression begins in the liver or the vascular endothelium, and whether its systemic increase in one area affects the onset or progression of the other. More research is necessary to determine whether VCAM-1 is merely a coincidental indicator of chronic inflammation in MASLD and SAH, or if it is a key mechanism driving the immunometabolic relationship between these two conditions.

TNF-α is a proinflammatory cytokine produced by monocytes and macrophages, with roles in immune response, apoptosis, and inflammation. It acts through two receptors, TNFR-1 and TNFR-2, found in nearly all cell types, including liver cells (85). In MASLD, KCs respond to hepatic injury, releasing TNF-α and attracting inflammatory monocytes. For decades, it has been established that TNF-α contributes to liver inflammation, fibrosis, hepatocyte apoptosis, and disease progression. However, it was recently proposed that the function of TNF-α in the liver may depend on its concentration. Zhao and colleagues demonstrated in a TNF ^−/− murine model treated with different concentrations of this cytokine that low levels of TNF-α reduce plasma indicators of liver injury, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), promote hepatocyte growth by modulating Yap activity protein, which is responsible for balancing cell proliferation and death in organs. However, these damage markers increased in a dose-dependent manner with TNF-α concentration, along with the phosphorylation and inactivation of Yap ( Figure 2A ) (86). Inhibition or deletion of TNF-α and/or its receptors in animal models enhances liver health by reducing fat accumulation and lowering ALT levels, decreases inflammation through reduced levels of IL-1β and IL-6, and improves insulin sensitivity by decreasing the activity of factors like JNK and NF-kB while exhibiting higher levels of adiponectin (87, 88). Clinical studies confirm elevated levels of TNF-α and its receptors in the liver and serum of patients with MASLD, which are linked to the severity of the disease (89).

Due to its systemic effects, dysregulation of TNF-α is associated with hepatic inflammation and other conditions characterized by chronic inflammation. One such condition is SAH, where TNF-α influences renal function by regulating hemodynamic and excretory processes, thus playing a role in the natriuretic response. This cytokine is implicated in vascular dysfunction and elevated BP. TNF-α contributes to the development of SAH by activating NADPH oxidase in polymorphonuclear leukocytes (PMN), producing oxidative stress. Moreover, TNF-α enhances Ang-2 signaling, driving renal and vascular dysfunction ( Figure 2B ) (90, 91). TNF-α inhibition with etanercept in salt-sensitive rat models diminishes the development of hypertension (92). Similarly, in patients with resistant hypertension, blocking TNF-α with infliximab reduces blood pressure (93), underscoring the pivotal role of this cytokine in the SAH pathophysiology. TNF-α is critical in MASLD and SAH, regulating inflammation and metabolic mechanisms. Therefore, targeting TNF-α could be a promising strategy for treating these chronic conditions.

IL-β is a pro-inflammatory cytokine with pleiotropic functions involved in inflammation and acquired immunity. It is produced as a precursor named proIL-1β, which requires enzymatic processing for activation, mediated by caspase-1 and the inflammasome. IL-1β is constitutively present in cells; however, its expression is induced by inflammatory stimuli such as Toll-like receptors (TLR) ligands or the release of alarmins. Following inflammasome activation, this cytokine is produced by resident macrophages and other myeloid cells (94). In the liver, KCs are responsible for producing IL-1β and expressing its receptor IL-1Ra. In liver failure and regeneration models, it was found that IL-1β inhibits liver regeneration while IL-1Ra promotes it (95). In animal models, the IL-1Ra deletion drives severe steatosis and fibrosis, highlighting the need for a balance between these molecules (96). IL-1β favors the progression of MASLD, allowing lipid accumulation in hepatocytes and increasing inflammation by the rise of neutrophil recruitment through the expression of intracellular adhesion molecule (ICAM-1) (97). Reducing IL-1β levels diminishes lipid accumulation in the liver (98). The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, a crucial component in liver inflammation and fibrosis, triggers the activation of IL-1β and IL-18. This activation is associated with disease progression in both animal studies and human cases of MASH (99, 100). IL-1β also contributes to advanced steps in the disease, specifically in fibrosis, by stimulating HSC, increasing tissue inhibitor of metalloproteinases 1 (TIMP-1) production, and preventing extracellular matrix degradation ( Figure 2C ).

Beyond liver disease, IL-1β-driven inflammation increases CVD risk. While IL-1β inhibition via canakinumab did not lower blood pressure in the CANTOS trial, it reduced cardiovascular events (101). Mechanisms by which IL-1β may drive hypertension include metalloproteinase 2 (MMP-2) activation, promoting vascular remodeling, sustained inflammasome activation, and extracellular matrix alterations that increase vascular stiffness (102). Atherosclerosis activates NLRP3 via cholesterol crystals and oxidized low-density lipoproteins (LDL) ( Figure 2D ), amplifying IL-1β release and cardiovascular inflammation (103). IL-1β also upregulates adhesion molecules and IL-6, contributing to systemic inflammation and elevated C-reactive protein levels (104).

IL-1β is a central mediator in the pathogenesis of MASLD and SAH. It promotes liver steatosis, fibrosis, and insulin resistance while contributing to systemic and vascular inflammation that underlies various forms of hypertension. Targeting IL-1β or its receptor presents a potential therapeutic strategy for reducing inflammation and preventing disease progression in hepatic and cardiovascular contexts.

IL-6 is a key pro-inflammatory cytokine produced by various cell types, including fibroblasts, monocytes, macrophages, T cells, endothelial cells, and KC, which contributes to the acute-phase response, host defense, and liver regeneration (105). IL-6 significantly contributes to the pathogenesis of MASLD. Both wild-type and IL6-deficient mice (IL6 ^-/-), when fed with a methionine and choline-deficient diet (MCD), developed steatohepatitis and experienced weight loss. Nevertheless, the IL6 ^-/- mice showed lower serum concentrations of liver damage markers, including ALT, and decreased blood glucose, cholesterol, and triglyceride levels. Despite developing similar levels of steatohepatitis as wild-type mice, the IL6 ^-/- mice exhibited less lobular inflammation. Furthermore, they showed lower levels of inflammatory markers, such as TGF-β and monocyte chemoattractant protein-1 (MCP-1). These findings suggest that IL-6 plays a crucial role in hepatic inflammation (106) IL-6 also promotes systemic IR through the upregulation of the suppressor of cytokine signaling 3 (SOCS-3). Elevated hepatic and serum IL-6 levels correlate with more significant inflammation, fibrosis, and insulin resistance in patients with MASH ( Figure 2E ) (107, 108).

It has also been reported that IL-6 receptor (IL-6R) concentrations decline in advanced stages of MASLD. They are associated with increased apoptosis in hepatocytes and leukocytes, suggesting IL-6R as a potential biomarker of MASLD progression (109) and in patients with obesity and MASH, increased soluble glycoprotein 130 (sgp130), which belongs to the IL-6 family, correlate with glycated hemoglobin (HbA1c), liver stiffness, and advanced fibrosis, indicating that glucose metabolic dysregulation may intensify IL-6 activity and worsen MASLD (110). In animal models, blocking IL-6/gp130 signaling prevents the progression to MASH. It reduces hepatic injury markers such as ALT and apoptosis despite increased lipid accumulation in the liver ( Figure 2E ), implying a dual role in protecting against MASH but enhancing inflammation (111).

Beyond liver disease, IL-6 is an established cardiovascular risk marker. It promotes arterial collagen synthesis and fibrinogen production and has been associated with coronary endothelial dysfunction (112) and atherosclerosis (113). In animal models, IL-6 administration led to cardiac dysfunction, hypertrophy, and fibrosis, effects observed independently of BP (114, 115). IL-6 inhibition using anti-interleukin-6 receptor antibody (MR16-1) improved left ventricular remodeling (116). Chronic infusion of growing doses of Ang-2 potentially stimulates the release of IL-6 through the renal Janus Kinases (JAK2/JAK3) signaling pathway, increasing the mean BP (117) ( Figure 2F ).

The relationship between IL-6, MASLD, and SAH has been little explored, but experimental evidence indicates a probable connection. The inflammatory properties of IL-6 could be key in the transition from MASLD to SAH, and additional research is required to elucidate this interconnection.

IL-17 is a proinflammatory cytokine produced by various immune cells in response to IL-1β and IL-23. The inflammatory effects triggered by IL-17 are typically controlled by regulatory T cells (Treg) and anti-inflammatory cytokines such as IL-10 and TGF-β (118). IL-17A plays a role in chronic low-grade inflammation, facilitating the progression from hepatic steatosis to MASH and liver fibrosis (119). In an HFD animal model, the inhibition of IL-17A reduces liver damage and inflammatory infiltration. Moreover, in hepatocytes in cultures exposed to FFA and IL-17A, this cytokine promoted steatosis by disrupting insulin signaling. Additionally, IL-17A activates HSC via extracellular signal-regulated kinases (ERK1/2) and p38 pathways, contributing to fibrosis (120). The exacerbated hepatic steatosis produced by IL-17A is caused by inhibiting fatty acid β-oxidation and promoting TG accumulation (121). Using therapeutic strategies targeting the IL-17A pathway and drugs that prevent the progression from MASLD to MASH, such as polyunsaturated phosphatidylcholine (PPC) and 3’,3’-diidolylmethane (DIM), restored the immune balance Th17/Treg reducing liver inflammation and the hepatic steatosis ( Figure 2G ) (122, 123). Blocking IL-17A and inhibiting Th17 cell differentiation in mice has demonstrated prevention of MASH and hepatocellular carcinoma (HCC), showcasing the therapeutic promise of IL-17A blockers (124).

Systemically, IL-17A contributes to vascular dysfunction and SAH by promoting oxidative stress, endothelial dysfunction, and vascular stiffness. It triggers inflammatory signaling pathways like NF-κB, p38 mitogen-activated protein kinases (MAPK), and RhoA/Rho-kinase (ROCK) (125), leading to higher collagen expression in vascular smooth muscle cells. Serum levels are increased in patients with SAH, especially in those with diabetes, HIV, or undergoing hemodialysis (126).

In humanized murine models, where the murine immune system was replaced with human hematopoietic stem cells (from bone marrow and liver) and human thymic cells, Ang-2 raises IL-17A levels, leading to vascular and renal inflammation (127). Blocking IL-17A reduces blood pressure, leukocyte infiltration, arterial remodeling, and renal dysfunction (128). IL-17A also regulates sodium transport in the kidneys, influencing natriuresis and blood pressure (129), contributing to endothelial dysfunction via the phosphorylation of the endothelial nitric oxide synthase (eNOS) (130), supporting the hypothesis that IL-17A plays a pathogenic role in the inflammation related to renal hypertension ( Figure 2H ).

IL-17A is an essential inflammatory mediator linking MASLD progression and SAH. It promotes steatosis, fibrosis, and IR in the liver while contributing to vascular inflammation and elevated blood pressure, making it a potential therapeutic target in both hepatic and cardiovascular diseases.