In the aging population, stroke has become a global concern (1). Subarachnoid hemorrhage (SAH) is the third most common subtype of stroke (2). The global mortality rate 25–35% (3). There are severe long-term neurological sequelae as cognitive ability may decline by >20% 1 year post-injury (4,5). Aneurysmal (a)SAH affects 6–9/100,000 individuals/year (6). According to the World Health Organization, the fatality rates 1, 2 and 7 days after the onset of SAH are 37, 60 and 75%, respectively (7). The cumulative mortality at 28 days in Australia is 26.7% (8) and 20–38% in Europe (9–11). The incidence rate of SAH in China is 2/100,000 individuals/year (12); additionally, it is estimated that the cumulative mortality at 28 days of aSAH in China is 16.9% (13). Considering the high mortality rate, it is important to pay attention to the complications following the SAH that contribute to mortality. Early case fatality are high across the world, which may increase by 50% in 2050 (1).

The pathophysiological mechanism of SAH is complex and multifactorial. Early brain injury (EBI) and delayed cerebral ischemia are key pathological processes following aSAH (14). Numerous clinical trials (14) have been conducted to improve outcomes for patients with aSAH, but there are challenges in aSAH prevention and the development of lower-risk treatments, these challenges persist in translating promising preclinical findings into effective low-risk treatments, partly due to issues with drug delivery across the blood-brain barrier and the multifactorial nature of early brain injury. The present aimed to summarize the pathogenesis and treatment for aSAH.

SAH is primarily divided into two stages: The pathophysiological changes with the first 72 h after SAH are called ‘EBI’ and the second pathological process that occurs 72 h after EBI involves delayed cerebral ischemia (DCI) which typically occurs days after the initial hemorrhage (15,16). EBI is the key factor affecting the prognosis of SAH (2,17). EBI primarily describes the pathological changes 72 h after aneurysm rupture: Blood leaks into the subarachnoid space following aneurysm rupture, followed by the rapid increase in intracranial pressure, acute vasospasm, decreased cerebral blood flow, disruption of brain autoregulation and brain swelling (15–17). It is triggered by primary disturbances such as hemorrhage, increased intracranial pressure, vasospasm, and decreased cerebral blood flow. These factors activate downstream pathological mechanisms, including oxidative stress, apoptosis, autophagy, and immune inflammation (14). These mechanisms lead to the formation of pro-inflammatory signals and metabolic disturbances in the brain, which are focal points for early neuroprotective strategies (18,19). EBI manifests via various secondary pathological cascades triggered by the primary insults of hemorrhage including microvascular dysfunction, blood-brain barrier (BBB) disruption, cerebral edema, neuroinflammation, oxidative stress, and neuronal death, leading to acute neurological deficit (17,18).

For example, the breakdown of heme releases toxic substrates that catalyze reactive oxygen species (ROS) production and activate neuroinflammation, further contributing to neuronal death (12). Additionally, blood in the subarachnoid space activates toll-like receptor 4 (TLR4) via the TLR4/NF-κB signaling pathway, which mediates neuroinflammation (20).

The upregulation of inflammatory cytokines enhances the expression of matrix metalloproteinase-9 (21,22), an enzyme that degrades tight junction proteins such as zonula occludens-1 (23). This degradation compromises the integrity of tight junctions, accelerating BBB disruption (24). Compromised BBB further promotes neuroinflammation, creating a cycle that exacerbates BI. Understanding these pathological mechanisms is essential for developing targeted therapeutic strategies to mitigate the impact of EBI and improve patient outcomes following aSAH.

TLR4 serves a key role in recognizing danger-associated molecular patterns (DAMPs), which are released following an aneurysm rupture. DAMPs markedly contribute to the increased permeability of the damaged BBB, leading to white blood cell infiltration, tissue edema and exacerbated BI (25). The activation of TLR4 initiates a series of signaling cascades that result in leukocyte activation and proliferation (26), further enhancing the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-8 and IL-12 (27).

Hemoglobin (Hb) degradation pathway, or the Hb-heme-iron axis, contributes to EBI. Hb degrades into heme, which breaks down into bilirubin and free iron (28). Free iron catalyzes ROS (29,30) production, and ROS-induced NLRP3 inflammasome activation triggers inflammatory responses (31). Excessive ROS production, coupled with decreased antioxidant defenses, results in cellular damage. Yue et al (30) revealed that in an intravascular perforation mouse model of SAH, ROS induces pyroptosis of neural stem cells (NSCs) by activating the NLRP3/gasdermin D (GSDMD) pathway. These findings indicate that Hb-induced NSCs may hinder nerve regeneration following SAH (32–35). Chang et al (36) used a mouse model of SAH to reveal that triiodothyronine (T3) treatment decreases mitochondrial ROS release, inhibiting neuronal apoptosis. These findings suggest that ROS is a potential therapeutic target for treating EBI following SAH (34,35). Studies (31,32) indicate that antioxidant treatment is an effective approach to mitigate EBI (Fig. 1).

TLR4 is the most well studied TLR and is widely expressed in the central nervous system (37–40). TLR4 serves out an important role in stroke-related inflammation (41). It is activated by the extravasated blood components in myeloid differentiation primary response-88/Toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-β (MyD88/TRIF)-dependent pathway (42) after SAH. Transcription factors initiated by the activation of TLR4, such as NF-κB, mitogen-activated protein kinase and interferon regulatory factor that regulate the expression of proinflammatory cytokine genes cause brain damage after SAH (43,44). These factors collectively regulate the expression of pro-inflammatory cytokine genes, which contribute to brain damage post-SAH (45–47).

Moreover, NF-κB is a key driver of inflammation, which increases the expression of inflammatory markers and matrix metalloproteinases (48) and contributes to the pathogenesis of intracranial aneurysm (IA) (49). In addition, NF-κB activation can lead to endothelial dysfunction (50,51). Furthermore, TLR4-mediated inflammation fosters smooth muscle cell phenotype switching (52–54) and promotes the infiltration of inflammatory cells in arterial walls, potentially leading to the occurrence and progression of IAs, which may result in rupture (55). Therefore, targeting the TLR4/NF-κB pathway presents a promising therapeutic strategy to mitigate EBI and delay BI associated with neuroinflammation following SAH, ultimately improving patient prognosis (47,49).

NLRP3-dependent signaling pathway serve a role in almost every mechanism of cell death, including pyroptosis (24,56–58). The NLRP3 inflammasome serves a role in the progression of injury following SAH (59,60). NLRs are a family of intracellular sensors of microbial motifs and ‘danger signals’ that serve as key components of innate immune responses and inflammation (61). Inflammasomes are multiprotein complexes that activate caspase-1. They process proinflammatory cytokines such as IL-1β. For a functional NLRP3 inflammasome, key components include a sensor protein (like an NLR), the adaptor protein ASC, and pro-caspase-1. ASC contains a CARD domain, which is important for recruiting pro-caspase-1 (62–64) and caspase-1 (65). GSDMD, a 53 kDa protein, is an inactive prerequisite protein in the cytoplasm, primarily composed of two domain groups, the C-terminal domain (CT-GSMD) and the T-terminal domain (NT-GSMD), which are connected by a flexible interdomain linker (66). After the aneurysm ruptures, heme groups of unstable extracellular Hb spontaneously oxidize to ferric methemoglobin and release superoxide in the reaction (67), which contributes to the production of ROS (68). The SAH model suggests that NLRP3 is activated by a common pathway of ROS (69,70). Activated NLRP3 inflammasomes recruit ASC and pro-caspase-1, further decompose and convert pro-caspase-1 into caspase-1 (71). Studies have demonstrated that caspase-1 can cleave the active linker (62,65,72), leading to the activation of the GSDMD protein and stimulating the secretion of the pro-inflammatory cytokines IL-1β and IL-18. The GSDMD protein also leads to the secretion of the pro-inflammatory cytokines IL-1β and IL-18 (71), as well as apoptotic and pyroptotic cell death (73). In addition, GSDMD is essential for both canonical and non-canonical inflammasome pathways (74) (Table I).

aSAH is a severe cerebrovascular event characterized by complex and multifaceted pathophysiological mechanisms, leading to high rates of morbidity and mortality. The present review summarized understanding of pathophysiology of aSAH and therapeutic strategies targeting the molecular pathways involved. Further research is required to translate these findings into clinical practice and improve outcomes for patients affected by aSAH.