Intracerebral hemorrhage (ICH) accounts for 10–15% of all strokes and usually refers to non-traumatic brain parenchymal hemorrhage. ICH is the second most frequent type of stroke after ischemic stroke, but has a much higher mortality rate [1, 2]. Hemorrhagic lacunar stroke accounts for 7.4% of ICH, with a symptom-free rate of 22.8% at discharge and a more favorable prognosis than ICH [3]. ICH survivors have a poor prognosis and a rate of high disability with reduced quality of life. Approximately 2.8 million people worldwide die from ICH every year [4]. The prevalence of ICH is higher in China than in Western countries and accounts for $>$25% of acute stroke patients [5]. Secondary brain injury (SBI) has been studied extensively with the aim of clarifying the damage mechanism and targets. This may lead to better clinical treatments and improved prognosis after ICH.

The lysosomal pathway mediates the process of autophagy, which breaks down macromolecules such as misfolded proteins in the cytoplasm and organelles. Moderate autophagy after ICH is protective against SBI, whereas excessive or insufficient autophagy causes harm. The key to discovering therapeutic targets is therefore to gain a better understanding of how to maximize the positive effects of autophagy. This paper focuses on the molecular mechanisms and regulation of autophagy.

ICH occurs mostly in the brainstem, lobes, basal ganglia and thalamus, with the most common site being the basal ganglia. Hypertension, diabetes and oral anticoagulants are known risk factors for ICH [6]. Cerebral amyloid angiopathy (CAA) is a common cause, while hematological disorders are also a special cause of ICH, especially in young people and in patients with unexplained recurrence. Routine blood cell counts, prothrombin time and activated thrombin time are important factors in relation to ICH [7]. SBI after ICH is mainly caused by primary and secondary mechanisms. Direct injury can occur early after ICH and is mostly associated with the formation of hematoma, which occupies and compresses the brain parenchyma, thereby destroying peripheral neural structures. SBI after ICH is mainly caused by ischemia and hypoxia in the ischemic penumbra surrounding the hematoma. SBI is associated with cerebral edema, inflammatory response and brain herniation [8]. Activation of thrombin and dysfunction of the blood-brain barrier (BBB) cause cytotoxic edema and vasogenic edema, resulting in perihematomal edema (PHE). The PHE grows rapidly in the early stages after ICH and is an important cause of intracranial hypertension [9]. Hematoma formation results in the activation of cytotoxicity and excitotoxicity. Hemoglobin, iron and other blood components also induce injury, while oxidative stress and inflammatory responses induce SBI, leading to neurological dysfunction. SBI after ICH leaves the patient with severe sequelae and functional impairment.

Autophagy is widespread in eukaryotic cells and was first detected in the 1950s by Christian de Duve using transmission electron microscopy. He observed that autophagy altered lysosome morphology and structure, and caused local degradation of the cytoplasm [10]. Autophagy is divided into three primary categories depending on the pathway by which substances enter lysosomes: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). These pathways coordinate, complement and work together to maintain cellular homeostasis. During macroautophagy, phagosomes with a bilayer membrane engulf part of the cytoplasm to form autophagosomes. These fuse with lysosomes to form autophagolysosomes, which are subsequently degraded by the action of lysosomal hydrolase. The degradation products are released and recycled for further use by the cells [11]. CMA is a highly selective process in which the molecular chaperone protein Hsc70 binds to a pentapeptide sequence target protein containing CMA recognition pentapeptide (KFERQ) and transports it to the lysosomal membrane. Here, it is recognized by the lysosomal-associated membrane protein 2A (LAMP-2A) and enters the lysosome to be degraded by lysosomal enzymes [12]. Microautophagy shares some similarities with CMA as a special type of autophagy, and some microautophagy is also associated with Hsc70 [13]. So far, microautophagy has mostly been studied in yeast, where lysosomal membrane invagination engulfs part of the cytoplasm directly into the lysosomes for degradation [14]. Most research on autophagy has been on macroautophagy, and hence this will be referred to here as autophagy.

Autophagy can be initiated under specific circumstances, such as nutrient starvation and oxidative stress. The initiation mechanism is conserved, and the formation of autophagosomes and autolysosomes is crucial to the process of autophagy. Autophagy initiation depends on the regulation of multiple factors, such as autophagy-related genes (ATGs). Autophagosomes have a bilayer vesicular structure whose formation is inseparable from the role of the endoplasmic reticulum (ER). ATG2 was shown to transfer lipid molecules from within the ER to autophagosomes. This process often occurs near the ER and may also involve other organelles that contain membrane structures [15, 16]. ATG9 located on the Golgi apparatus is the sole transmembrane protein amongst the autophagy-related proteins [17]. The Golgi apparatus plays a role in the formation of autophagosomes by regulating ATG9 transport, and the autophagic signaling pathway involves Golgi apparatus proteins [18]. Through a process of extension and expansion, phagosomes engulf and degrade small parts of the cytoplasm containing specific proteins and organelles to form autophagosomes. The uncoordinated 51-like kinase 1 (ULK1) complex and the Beclin-1 class III phosphatidylinositol-3-kinase (PI3KC3) complex are the two main protein complexes involved in the initiation of autophagy [19]. Light chain 3 (LC3) is a soluble protein that regulates autophagic flux and can be used as a marker of autophagy. The two variants of LC3 are LC3-I, which is the cytosolic type, and LC3-II which is the membrane-bound type. LC3 transforms into LC3-I under the action of ATG4 [20]. Upon the initiation of autophagy, LC3-I is transformed into LC3-II, and the formation of autophagosomes is related to the ratio of LC3-II to LC3-I. One of the most crucial organelles in autophagy is the lysosome, since it provides an acidic environment and various hydrolysis enzymes to degrade specific substrates. The fusion of autophagosome membranes to lysosomes results in the formation of autophagolysosomes. This process is negatively regulated by mammalian target of rapamycin complex 1 (mTORC1) [21]. As shown in Fig. 1, the contents of autophagolysosomes can be reused after degradation.

Fig. 1.

Molecular mechanisms of autophagy initiation. Autophagy is activated when the body undergoes adverse reactions such as oxidative stress and inflammatory responses. The uncoordinated 51-like kinase 1 (ULK1) complex and the class III phosphatidylinositol-3-kinase (PI3KC3) complex adenosine 5${}^{\prime }$-monophosphate (AMP)-activated protein kinase (AMPK), mTOR, and the B-cell lymphoma 2 (Bcl-2)/Beclin-1 signaling pathway. Phagosome extension engulfs misfolded proteins and organelles and fuses them with lysosomes to form autophagosomes. Light chain 3 (LC3) is converted to LC3-I by autophagy-related gene 4 (ATG4). LC3-I can be cleaved enzymatically to convert into LC-II. LC-II acts together with ATG9 and ATG12-5-16 complexes to expand and fuse autophagosome and lysosome membranes in a process that depends on the endoplasmic reticulum. mTOR, mammalian target of rapamycin; AKT, protein kinase B; PI3K, phosphatidylinositol-3-kinase; MAPK, mitogen-activated protein kinase.

A number of pathogenic responses are induced by ICH. These include oxidative stress and inflammation [22, 23], as well as iron overload and ER stress [24, 25]. These pathological reactions can affect autophagy when they occur. Neutrophils can also release proinflammatory proteases that aggravate the pathological damage from ICH. A high neutrophil-to-lymphocyte ratio is associated with poor prognosis in ICH patients [26, 27]. Activated neutrophils, microglia, and macrophages produce excess reactive oxygen species (ROS) following ICH [28]. ROS accumulation can in turn cause oxidative stress and break the normal balance between oxidan and antioxidant, thereby aggravating SBI after ICH. ROS can also induce the onset of autophagy. Degradation of the products of oxidative stress by phagocytosis can regulate excess free radicals such as ROS, thus mitigating SBI after ICH. This process involves multiple pathways, including p62, CMA and the mitochondrial pathway [29, 30]. Oxidative stress can also cause iron overload [31], and autophagy induced by ICH is significantly influenced by iron. Erythrocytes lyse following ICH, resulting in massive accumulation of free iron [32] that can lead to increased ROS, thus exacerbating SBI. Premenopausal women have higher survival rates after ICH than men. Estradiol protects brain tissue, participates in the inhibition of autophagy, and reduces SBI, which is also associated with iron overload [33]. Heme oxygenase-1 (HO-1) can also induce excessive iron production which then aggravates brain damage [34]. Autophagy is activated in various brain cells after ICH. Thrombin is a serine protease that can cause autophagy in astrocytes and brain cells [35] by increasing the conversion of LC3-I to LC3-II. The LC3-II to LC3-I ratio is increased on the third day after ICH, indicating that autophagy has begun. Hematoma is the main cause of inflammatory response after ICH, with microglia and other inflammatory cells such macrophages also being significant contributors [36]. Microglia activation and autophagy are mediated by toll-like receptor 4 (TLR4). Hematomas causes TLR4 to activate signaling pathways, resulting in inflammatory damage [37, 38]. Interleukin-17A (IL-17A) is involved in mediating autophagy and inflammation during treatment for ICH [39]. NOD-like receptor thermal protein domain associated protein 6 (NLRP6) belongs to the family of NOD-like receptors (NLRs) that are involved in the regulation of inflammation. Han Xiao et al. [40] observed increased NLRP6 expression after the onset of ICH in an experimental model. Downregulation of NLRP6 expression can reduce autophagy and the inflammatory response, which is inextricably linked to oxidative stress [41]. Oxidative stress promotes the occurrence of an inflammatory response. Pro-inflammatory cytokines resulting from ROS can activate the c-Jun N-terminal kinase (JNK) and tumor necrosis factor (TNF) induced nuclear factor kappa-B (NF-$\kappa$B) signaling pathway [42]. Conversely, inflammatory responses can affect oxidative stress. The TNF-induced NF-$\kappa$B signaling pathway is important in reducing intracellular ROS levels, and the coordination between these is important after ICH. Experiments have confirmed that autophagy increases 6 h after ICH. When ER stress is present, autophagy increases further and participates in caspase12-mediated apoptosis. One week after ICH, autophagy inhibits ER stress, reduces neuronal apoptosis and necrosis, and protects the cerebral nerves [43]. The incidence of ICH increases with age, but shows a downward trend after 85 years of age [44]. Yotam Raz et al. [45] reported that autophagy can still occur in centenarians. Both insufficient and excess autophagy may lead to neuronal cell death. Excessive autophagy in the early stages of ICH can harm the brain, while its inhibition can preserve the brain. Autophagy is involved in maintaining cellular homeostasis in the latter phases of ICH, thereby protecting against brain injury [46].

There are two sides to autophagy following ICH. On one hand it can induce programmed cell death, and on the other it can affect cell survival. This is closely related to the level of autophagy, where either insufficient or excessive autophagy can lead to neuronal cell death. Excessive autophagy leads to SBI early during the onset of ICH. It has been confirmed experimentally that autophagy increases 6 hours after ICH. This rises even further due to the involvement of ER stress, which participates in caspase12-mediated apoptosis [43]. Autophagy is induced by ROS, and it also regulates free radicals such as excess ROS to mitigate SBI after ICH. This process involves multiple pathways including p62, CMA, and the mitochondrial pathway. Inhibition of autophagy reduces microglia activation and the inflammatory response, and attenuates brain injury. Interleukin broadly regulates the immune response in ICH. Regulation of the expression of anti- and pro-inflammatory factors improves the prognosis of IL. IL-6 is a pro-inflammatory cytokine and elevated levels can increase the risk of hematoma expansion, resulting in impaired recovery and affecting patientoutcome [47]. IL-10 is an anti-inflammatory mediator that regulates the levels of B-cell lymphoma 2 (Bcl-2) and Bax to reduce inflammation and apoptosis, thereby helping to repair nerve damage [48]. IL-33 often acts on microglia and macrophages and can increase the level of anti-inflammatory factors by decreasing the release of pro-inflammatory factors. IL-33 reduces neuronal apoptosis by increasing Bcl-2 and decreasing caspase-3. IL-33 can inhibit autophagy and reduce brain injury by increasing the level of p62, reducing the expression of autophagy-related proteins LC3-II and Beclin-1, and inhibiting expression of the pro-inflammatory cytokines IL-1$\beta$ and TNF-$\alpha$ [38]. Autophagy has a detrimental effect on ICH, and therefore inhibition of autophagy can have a protective effect in the brain.

The benefit of autophagy after ICH lies in its ability to maintain intracellular homeostasis, thus providing a neuroprotective effect in brain injury [46]. Although autophagy is activated in response to oxidative stress, it also degrades oxidative stress products through phagocytosis, regulates ROS levels, and attenuates SBI caused by oxidative stress. Thrombin is produced immediately after the onset of ICH and disrupts the blood-brain barrier, thus causing edema. Autophagy plays a protective role against thrombin-induced brain injury. One week after ICH, autophagy inhibits ER stress, reduces neuronal apoptosis and necrosis, and protects brain nerves. $\alpha$7nAChR can trigger the cholinergic anti-inflammatory pathway (CAIP) to reduce the inflammatory response. Activation of $\alpha$7nAChR increases Beclin expression, increases the LC3-II/LC3-I ratio, reduces p62/Sequestosome 1 (SQSTM1), and enhances autophagy. These confer cerebral protection through autophagy and improve cardiac dysfunction following ICH [49]. Another study [50] reported that hypoxic preconditioning could upregulate autophagy, promote stem cell proliferation, and enhance neural regeneration after ICH in a process that involved miR-326. MiR-326 mediated autophagy delayed the senescence of olfactory mucosa mesenchymal stem cells (OM-MSCs) during treatment for ICH.

Under normal physiological conditions, autophagy maintains the energy balance by regulating metabolism and maintaining body homeostasis. Autophagy can have both destructive and protective functions in ICH due to regulation by a variety of signaling pathways. These include the mTOR, adenosine 5${}^{\prime }$-monophosphate (AMP)-activated protein kinase (AMPK), PI3K, mitogen-activated protein kinase (MAPK), and Beclin-1/B-cell lymphoma 2 (Bcl-2) signaling pathways.

Autophagy and the ubiquitin-proteasome system (UPS) are two pathways involved in the metabolism of damaged proteins (Fig. 2). UPS acts on the proteasome, while autophagy acts on proteins within the lysosome. Both processes are highly specific and maintain protein homeostasis under both physiological and pathological conditions [112, 113]. UPS is distinct from autophagy in that it is a non-lysosomal pathway consisting of ubiquitin, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), ubiquitin ligase (E3), deubiquitinating enzyme (DUB) and the proteasome. Ubiquitin contains 76 amino acid residues covalently bonded to the protein substrate following a ubiquitination cascade reaction that labels the target protein [114, 115]. ATP supplies the energy and ubiquitin is activated to produce a thioester link with E1. E1 transfers ubiquitin to E2 to form an E2-ubiquitin complex via a generated thioester bond. E3 selectively recognizes the substrate and acts on the E2-ubiquitin complex to bind it to ubiquitin. The resulting ubiquitinated protein substrate is eventually recognized by the proteasome for degradation in a reversible process. DUBs act specifically between the ubiquitin and the protein substrate to sever the ubiquitin chain structure [116, 117]. Although they act independently, the UPS and autophagy pathways nevertheless intersect with each other [118]. The autophagy receptor p62 links UPS with autophagy. P62 is a ubiquitin-binding protein involved in proteasomal degradation while also simultaneously activating Nrf2 signaling [119]. The triangle motif (TRIM) family member TRIM44 is known to connect UPS to autophagy. De-ubiquitination of TRIM44 oligomerizes SQSTM1, which acts on autophagy-associated structures to activate autophagy [120]. Regulators involved in autophagy, such as the ubiquitin ligase TRAF6, ubiquitinate K63 ULK1 to promote the initiation of autophagy. TRAF6 ubiquitinates K63 of Beclin-1 to prevent it from binding to Bcl-2, thus promoting autophagy [121, 122]. Luteolin has neuroprotective effects and reduces brain edema. It can be used to treat brain damage caused by the inflammatory response and oxidative stress after ICH. Luteolin inhibits ubiquitination of TRAF6 and Nrf2, enhances autophagy, and activates the p62/Keap1/Nrf2 pathway to exert neuroprotective effects [123, 124].

Fig. 2.

Autophagy and UPS. Autophagy and UPS are important protein degradation pathways in human cells. In UPS, ubiquitin molecules covalently bind to the substrate protein under the cascade catalysis of ubiquitin-activating enzyme (E1), ubiquitin-conjugation enzyme (E2) and ubiquitin-protein ligase (E3). UPS, ubiquitin-proteasome system; ATP, adenosine triphosphate; AMP, adenosine monophosphate.

The selective recognition, isolation and degradation of specific protein aggregates or damaged organelles via the autophagic pathway is called selective autophagy. This process serves to remove unwanted material from the cell and maintain intracellular homeostasis. Selective autophagy includes mitophagy, peroxisomal autophagy, ER autophagy, ribosomal autophagy and lipid autophagy. These represent different types of autophagy in different cellular organelles and in response to different stresses [125, 126]. Ubiquitin can also degrade protein aggregates via selective autophagy. The p62/SQSTM1 protein can acts as a selective autophagy receptor and is important in signaling, differentiation, and the removal of protein aggregates. P62 can bind directly to LC3 at the site of autophagic vesicle production to mediate selective autophagy. It associates with ubiquitinated proteins, delivers ubiquitinated protein aggregates to autophagic vesicles, and degrades ubiquitinated substrates [127]. mTORC1 and the Keap1/Nrf2 signaling pathway are both crucially activated by p62 during the process of selective autophagy. Phosphorylated p62 competes for Nrf2 binding sites during Keap1/Nrf2 signaling under the mediation of mTORC1 to inhibit Nrf2 degradation and induce the expression of cytoprotective Nrf2 targets [128, 129]. Toll-like receptor-4 (TLR4) stimulates the transcription of p62/SQSTM1 via the NF-$\kappa$B signaling pathway and hence its participatione in autophagy [130]. P62 can also interact with ATG8 attached to the phagosomal membrane. ATG8 is coupled to phosphatidylethanolamine (PE) and modifies autophagosomes [131, 132]. Moreover, ATG8 is involved in the recruitment of specific autophagy receptors with an ATG8-interacting motif (AIM). Excessive or damaged mitochondria, peroxisomes, ER, ribosomes, and lipid receptors can act as ATG-binding proteins and induce selective autophagy through high affinity ubiquitin-interacting motif (UIM)-targeted binding to ATG8 [133, 134]. Selective autophagy plays a broad role in physiology and pathology, including the removal of protein aggregates and damaged mitochondria. It is also critical for maintaining functional stability of the nervous system [135, 136].

8.1 Mitophagy

Mitochondrial autophagy, or mitophagy, is a specific type of autophagy that maintains mitochondrial homeostasis by selectively identifying and removing dysfunctional and damaged mitochondria [137]. Mitophagy is the most common type of selective autophagy in neurological diseases and occurs in numerous physiological and pathological conditions. Lemaster first proposed mitophagy as a quality control mechanism in 2005 [138]. Mitochondria is involved in SBI after ICH, while oxidative stress, inflammatory response, mitochondrial permeability transition pore (mPTP) opening, mtDNA damage, and Ca${}^{2+}$ overload are closely associated with mitochondrial dysfunction. Mitophagy is therefore an important therapeutic target for ICH [139]. It can be activated via a number of different pathways (Fig. 3), with the classical one being the PINK1/Parkin pathway. Mitochondrial-targeted PINK1 acts upstream of the E3 ubiquitin ligase Parkin. Phosphatase and tensin homolog (PTEN)-induced kinase 1(PINK1) is normally located in the mitochondria, but mitochondrial damage leads to its activation and accumulation in the outer mitochondrial membrane. Parkin is located in the cytoplasm, phosphorylated by PINK1, and is recruited to damaged mitochondria. The conditions for initiation of autophagy are provided by the subsequent ubiquitination of Parkin [140, 141, 142]. Jingchen Li et al. [143] showed that PINK1 promotes mitophagy in microglia, thus protecting against brain injury after ICH. NLRP3 inflammatory vesicles are closely related to mitophagy and can be triggered by excess ROS and calcium overload. Parkin activates mitophagy and inhibits ROS production, thereby suppressing NLRP3 inflammatory vesicle-mediated inflammation [144]. The AMPK, FUN14 domain containing 1 (FUNDC1), PI3KIII and Bcl2/E1B 19 kDa-interacting protein 3/NIP3-like protein X (BNIP3/NIX) pathways can also activate mitophagy. AMPK phosphorylates ULK1 to promote mitophagy and is also involved in regulation mitochondrial homeostasis. FUNDC1 is an outer mitochondrial membrane (OMM) protein that is activated under hypoxic conditions. FUNDC1 inhibits the activation of NOD-like receptor protein 3 (NLRP3) inflammatory vesicles by promoting mitophagy, thereby reducing brain damage after ICH [145]. BNIP3 and its analogue NIX are both OMM proteins that contain an LC3-interacting region (LIR). BNIP3/NIX binds to ATG8 via the LIR sequence and recruits ATG8 to targeted mitochondria, thus activating mitophagy [146, 147, 148]. Scalp acupuncture can prevent brain tissue damage after ICH and reduce apoptosis by activating mitophagy through the PI3KIII, PINK1/Parkin and NIX pathways [149].

Fig. 3.

Molecular mechanisms of microglia. When mitochondria are damaged, the main receptors on microglia are PINK1, BNIP3, NIX and FUNDC1. PINK1 accumulates in the outer mitochondrial membrane and recruits Parkin to the mitochondria, where it is then activated. BNIP3 and NIX are also located on the outer mitochondrial membrane and their levels increase in response to upstream signaling factors. The LIR site of BNIP3 and NIX is on the cytoplasmic side and activates microglia by binding to LC3. FUNDC1 enhances the interaction with LC3 under hypoxic conditions and upregulates microglia. PINK1, Phosphatase and tensin homolog (PTEN)-induced kinase 1; LC3, Light chain 3; FUNDC1, FUN14 domain containing 1; NIP3-like protein X (NIX); BNIP3, Bcl2/E1B 19 kDa-interacting protein 3-like protein.

The mechanism underlying mitophagy involves many complex pathways, while the specific mechanisms involved in SBI after ICH are still to be clarified. The role of mitophagy is two-fold. Moderate autophagy is beneficial to the organism, whereas excessive autophagy can have harmful effects. Mitophagy may therefore be a valuable therapeutic target in the future.

Autophagy occurs in different cell types after ICH, but is mainly concentrated in microglia, astrocytes and neurons. Autophagy protects injured neurons but also affects the clearance of harmful cells, leading to SBI.

Chenghan Wu et al. [165] used transmission electron microscopy and autophagy-related protein labeling to observe autophagy of neurons around the hematoma in patients with ICH. The level of autophagy was positively correlated with the degree of nerve cell dysfunction and the amount of bleeding. Thrombin is involved in the activation of autophagy. Targeted autophagy intervention in clinical practice may lead to better patient outcomes. Central post-stroke pain is due to vascular injury caused by bleeding or ischemia and can be relieved by oral antidepressants. Acupuncture regulates the activation of glial cells and apoptosis of neuronal cells, while affecting the transmission of neurotransmitters that have analgesic effects. Ling Zheng et al. [167] used electroacupuncture to inhibit autophagy in the hippocampus, which proved effective in relieving post-stroke pain. Yue Su et al. [49] showed that activation of $\alpha$7nAChR could improve brain edema and neurological function after ICH.

The treatment of cerebral hemorrhage and mitigation of SBI remain crucial to the survival and recovery of patients with ICH, but the pathophysiological processes involved are complex. Increasing experimental evidence has confirmed that autophagy is involved in oxidative stress and inflammatory response, and that autophagy could be used as a potential therapeutic target to reduce SBI. Relevant trials on the treatment of ICH are shown in Table 1 (Ref. [39, 50, 108, 123, 168, 169, 170]). However, the role of autophagy is inconsistent and it may have different effects at different stages of ICH. Knowledge gaps remain in how to regulate autophagy, how to avoid the harmful effects of autophagy, and how to avoid damage to the brain and other organs so that it can be used optimally in the treatment of ICH.

In conclusion, autophagy is a double-edged sword with varying outcomes depending on the stage of ICH. Autophagy is used to clear necrotic tissue cells. On the flip side, an excess of autophagy results in more severe brain injury. Autophagy does not have a single role and is instead an important part of a series of pathological reactions secondary to ICH. It is influenced by a number of factors including initiating events, areas of activity, and related effects. Research in this area has advanced significantly, but many of the mechanisms remain to be clarified. For the effective treatment of ICH, it is essential to control autophagy by specific initiation or inhibition at specific sites in order to prevent harmful effects and to avoid damage to the brain and other organs. Key to the outcome of ICH is the identification and selection of critical time points, having effective means to control harmful autophagy, and using autophagy in a beneficial manner. Elucidation of the mechanism of autophagy in nerve cells requires further research. Neuroinflammation and autophagy are important mechanisms in the synergistic treatment of ICH, and the aim is to reduce the inflammatory response through autophagy to obtain better patient outcomes. Autophagy and selective autophagy are regulated by a variety of cytokines, and their molecular mechanisms and signaling pathways show considerable diversity. With the exception of mitophagy, there have so far been few studies on selective autophagy following cerebral hemorrhage. The binding receptor could also be explored as a potential therapeutic target. Autophagy could therefore be clinically useful as a therapeutic target for SBI after ICH. However, current research is still insufficient and further studies in this area are needed.

ICH, intracerebral hemorrhage; SBI, secondary brain injury; CAA, cerebral amyloid angiopathy; BBB, blood-brain barrier; PHE, perihematomal edema; CMA, chaperone-mediated autophagy; LAMP-2A, lysosomal-associated membrane protein 2A; ATGs, autophagy-related genes; ER, endoplasmic reticulum; ULK1, uncoordinated 51-like kinase 1; PI3KC3, Beclin1 class III phosphatidylinositol-3-kinase; LC3, light chain 3; mTORC1, mammalian target of rapamycin complex 1; AKT, protein kinase B; ROS, reactive oxygen species; HO-1, heme oxygenase-1; TLR4, toll-like receptor 4; NLRs, nod-like receptors; JNK, c-Jun N-terminal kinase; TNF, tumor necrosis factor; NF-$\kappa$B, nuclear factor kappa-B; IL-17A, interleukin-17A; CAIP, cholinergic anti-inflammatory pathway; SQSTM1, Sequestosome 1; AMP, adenosine monophosphate; AMPK, AMP–activated protein kinase; MAPK, mitogen-activated protein kinase; Bcl-2, B-cell lymphoma 2; PIKK, PI3K-associated protein kinase; DEPTOR, DEP domain-containing mTOR-interacting protein; mLST8, mammalian lethal with SEC13 protein 8; RAPTOR, regulatory-associated protein of mTOR; PRAS40, 40 kDa Pro-rich Akt substrate; RICTOR, rapamycin-insensitive companion of mTOR; mSIN1, mammalian stress-activated map kinase-interacting protein 1; PROTOR1, protein observed with RICTOR1; ATP/AMP, adenosine triphosphate/adenosine monophosphate; CaMKK$\beta$, Ca${}^{2+}$/Calmodulin-dependent protein kinase kinase$\beta$; TSC2, tuberous sclerosis complex2; DRAM, damage-regulated autophagy modulator; PTEN, phosphatase and tensin homolog; ERK1/2, extracellular-signal-regulated kinase1/2; MKK3, MAPK kinase 3; LAMP2A, lysosome-associated membrane protein 2A; LPS, Lipopolysaccharide; CCR1, C-C chemokine receptor type 1; Nrf2, nuclear factor-E2-related factor 2; BAG2, BCL2-associated thymus gene2; UPS, ubiquitin-proteasome system; E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin ligase; DUB, deubiquitinating enzyme; TRIM, triangle motif; PE, phosphatidylethanolamine; AIM, ATG8-interacting motif; UIM, ubiquitin-interacting motif; ALS, amyotrophic lateral sclerosis; mPTP, mitochondrial permeability transition pore; PINK1, phosphatase and tensin homolog (PTEN)-induced kinase 1; FUNDC1, FUN14 domain containing 1; OMM, outer mitochondrial membrane; BNIP3/NIX, Bcl2/E1B 19 kDa-interacting protein 3-like protein; NLRP3, NOD-like receptor protein 3; NCOA4, Nuclear receptor coactivator 4; NBR1, neighbor of BRCA1 gene 1; TAX1BP1, Tax1 (human T cell leukemia virus type I) binding protein 1; LIR, LC3-interacting region; CNS, central nervous system; PTBP1, polypyrimidine tract-binding protein 1; TRAF6, TNF receptor-associated factor 6.

JZ, WZ and XPY conceptualized and designed the study. JZ designed the figures and conducted a literature review. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

Not applicable.

This work was supported by the National Natural Science Foundation of China (Grant No. 81774416).

The authors declare no conflict of interest.