Environmental stimuli, immune signals, and metabolic status are the primary upstream signals that activate mTOR (23). Various pathways are associated with mTORC1 activation, such as phosphoinositide 3-kinase (PI3K)/AKT, adenosine 5′-monophosphate-activated protein kinase (AMPK), tuberous sclerosis complex1 (TSC1)/TSC2/Ras homolog enriched in brain (RHEB), VAM6/Rag GTPase, and others (24). RHEB is a GTPase embedded in the lysosome membrane whose activity depends on the type of nucleotide it binds to. mTORC1 can be recruited to the lysosome and activated directly through GTP attachment to RHEB (25, 26).

Environmental stimuli, specifically signals from growth factors, insulin, and insulin-like growth factors, are efficient activators of mTORC1, predominantly mediated by the PI3K/AKT pathway (27). Receptor tyrosine kinases (RTKs) stimulated by growth factors activate PI3K to enable the production of phosphatidylinositol 3,4,5 trisphosphate (PIP3), which transfers the activating signals to phosphoinositide-dependent kinase 1 (PDK1) and AKT (28, 29). TSC acts as a GTPase-activating protein by promoting the conversion of GTP to GDP by irritating the GTPase activity of RHEB to alter its nucleotide binding state to the inactive mode and indirectly inhibits mTORC1 (30). In brief, TSC is suppressed by the PI3K/AKT pathway to facilitate the positive effect of RHEB on mTORC1. Furthermore, downstream of RTKs, the Ras/Erk/p90 RSK1 axis acts as both a direct and indirect activator of mTORC1 by inhibiting TSC and phosphorylating RAPTOR, respectively (31–34).

Antigens, cytokines, and various other immune signals are the main stimulators of mTORC1 activation (35, 36). For example, a toll-like receptor (TLR) is triggered by its legend and conveys the activating signals to mTORC1 through the PI3K/AKT pathway (37, 38).

Considering the critical role of mTOR in metabolism, changes in energy and nutrient abundance are expected to regulate mTORC1. Under the circumstances of glucose starvation or energy depletion, the ratio of AMP to ATP increases due to a decline in ATP, facilitating AMPK activation. AMPK can enhance the inhibitory effect of TSC on mTORC1 by phosphorylating TSC (39). Moreover, it has been shown that mTORC1 is inhibited directly by AMPK by phosphorylating RAPTOR (40).

In addition to glucose, intracellular amino acid levels activate mTORC1, which is mediated by the RAS-related GTP binding protein (RAG)/Ragulator pathway. The heterodimer consisting of RAG A/B and RAG C/D can be ligated to the lysosome with Ragulator as a bridge and transformed to its active state with GTP and GDP attached to RAG A/B and RAG C/D, respectively (41, 42). The RAG heterodimer promotes the transposition of mTORC1 to lysosomes and activates it, whereas GATOR1 suppresses mTORC1 activation by inhibiting RAG A/B (42, 43). GATOR2 can counteract the negative effect of GATOR1 on mTORC1 (43). Sestrin2, when bound to leucine, is deprived of the ability to restrain GATOR2 and mediates the effect of leucine on mTORC1 activation, which gives rise to the interaction between GATOR1 and GATOR2 to activate mTORC1 (44–46). CASTOR1 can detect intracellular arginine, mitigating its suppressive role in GATOR2 to activate mTORC1 indirectly (47). The arginine inside the lysosome activates mTORC1 by interacting with the RAG-Ragulator complex; v-ATPase assists in perceiving changes in arginine levels (48–50). Glutamine activates mTORC1 in both a RAG-dependent and -independent manner. Glutamine is decomposed during glutaminolysis, which yields α-ketoglutarate (α-KG), enabling loading of GTP to RAG B by prolyl hydroxylases (PHDs) (51). The breakdown process also contributes to ATP generation and serves as a bioenergetic resource to ameliorate AMPK-induced mTORC1 inhibition (52, 53). Increasing evidence has substantiated that mTORC1 is activated by glutamine independently of RAG through ADP-ribosylation factor-1 (Arf1), which promotes the recruitment and translocation of mTORC1 to lysosomes (51, 54, 55).

Regarding the mechanisms underlying the activation of mTORC2, it has been well established that PI3K functions upstream of mTORC2 via PIP3, which binds to mSin1 and reverses its inhibitory effect on mTOR to activate it (56). Furthermore, PI3K strengthens the interactions between mTORC2 and the ribosome, which serves as the site of mTORC2 activation (57). In contrast to mTORC1, mTORC2 is activated by AMPK with glucose withdrawal (58). However, more in-depth research on mTORC2 activation is in high demand.

As a key regulator of cellular metabolism and growth, mTORC1 can promote anabolism and inhibit catabolism by controlling the synthesis of proteins, nucleotides, and lipids (59). This part of the review focuses on regulating protein synthesis by mTORC1.

p70-S6 kinase 1 (p70-S6K1) and 4E binding protein 1 (4E-BP1) are the main substrates of mTORC1 and are pivotal to translation. mTORC1 activates p70S6K through phosphorylation, which increases gene expression and protein synthesis by activating various substrates implicated in mRNA maturation and translation. 4E-BP1 inhibits protein production by binding to eukaryotic initiation factor 4E (eIF4E) to block transcription. 4EBP phosphorylated by mTORC1 results in the loss of its affinity for eIF4E, thus reversing its negative effect on transcription and protein synthesis (60–62).

Some substrates of mTORC2 have been identified, including AKT, serum and glucocorticoid-induced protein kinase 1 (SGK1), and protein kinase C-α (PKC-α) (63–65). AKT functions upstream of NF-κB, Bad, and FOXO to regulate cell death. SGK1 and PKC-α activated by mTORC2 are associated with cytoskeleton remodeling and migration (66–68).

A necrosome composed of RIPKs is required for necroptosis, with activated MLKL serving as the executor of membrane perforation. RIPK1 comprises the N-terminal kinase, intermediate domain, and C-terminal death domain (DD). Several regulatory sites exist in the intermediate domain, such as ubiquitination sites and RIP homotypic interaction motifs (RHIM) (69, 70). RIPK3 and RIPK1 share a similar molecular structure; however, the C-terminal domain of RIPK3 does not encompass DD, which differs from RIPK1 (71). MLKL activated by RIPK3 is integral for the terminal stage of necroptosis. MLKL can form an amyloid-like oligomer that translocates to the plasma membrane and mediates membrane perforation (72, 73).

Necroptosis is initiated by binding the corresponding ligand to the death receptor. Death receptors, belonging to the TNFR (TNF receptor) superfamily, receive and transduce several extracellular signals, including FasL, TNFα, TNF-related apoptosis-inducing ligand (TRAIL), and so on, among which the TNFα-induced mechanism has been studied most thoroughly (74, 75). In addition to death receptors, pattern-recognition receptors (PRRs), such as TLR3 and TLR4, contribute to necroptosis induction by recognizing relevant pathogen-associated molecular patterns (PAMPs) (76, 77). This section provides an overview of the mechanisms of necroptosis induced by various signals (Figure 2).

More novel types of cell death have been discovered gradually, including apoptosis, necroptosis, pyroptosis, ferroptosis, and so on. It is pertinent to emphasize the conditions under which favor necroptosis.

Pan-caspase inhibitor Z-VAD-FMK ignited the switch from apoptosis to necroptosis (2). More initiators of necroptosis have been discovered, which partially overlap with those of extrinsic apoptosis and can be roughly categorized into two groups. One group is dominated by death receptors, including TNFR1, Fas, and TRAILR (72, 124, 125). The other one consists of the receptors which contain the RHIM domain and activate RIPK3 directly (76, 77, 126).

Activated death receptors induce the constitution of complex I (TNFα-TNFR1 and TRAIL-TRAILR) or DISC (FasL-Fas), which triggers extrinsic apoptosis and necroptosis (79). Complex I transfers a pro-survival signal through NF-κB (88). When NF-κB is blocked or RIPK1 is deubiquitinated, complex I shifts to complex II, causing extrinsic apoptosis (127, 128). Inactivating caspase-8 can tip the balance in favor of necroptosis through RIPK1-RIPK3 interaction and necrosome assembly (82, 129). In addition, some RHIM-containing factors activate RIPK3 directly. TLR3 and TLR4 recruit TRIF to activate RIPK3 through the RHIM domain. ZBP1 activated by Z-DNA is another mediator of necroptosis through direct interplay with RIPK3 (130, 131).

Autophagy plays an integral role in the regulation of necroptosis. mTORC1 has been universally recognized as an autophagy inhibitor through various mechanisms, such as phosphorylating unc-51-like kinase 1 (ULK1), interrupting transcription factor EB (TFEB) translocation to nuclear, and interfering with lysosome reformation (159, 160). Thus, autophagy serves as a bridge for mTOR to regulate necroptosis (Figure 3).

Autophagy disrupts the interaction between RIPK1 and RIPK3 to inhibit necroptosis. Di Ge et al. verified that 11-methoxytabersonine (11-MT) induced necroptosis in A549 and H157 cell lines, and autophagy was also initiated by activating the AMPK/mTORC1 pathway (161). 3-methyladenine (3-MA) and chloroquine (CQ), both of which inhibit autophagy, were utilized to investigate the relationship between autophagy and necroptosis in detail. The combined administration of 11-MT and autophagy inhibitors may intensify the interaction between RIPK1 and RIPK, thereby accelerating necroptosis, which confirmed that mTORC1 promoted necroptosis by downregulating autophagy (161).

Autophagy also has a prominent influence on the levels of cellular RIPKs to inhibit necroptosis. RIPK1 and MLKL are suppressed by increased autophagy resulting from inactivated PI3K/AKT/mTOR/p70S6K pathway (162). AMPK-mTOR is a potential target for treating spinal cord injury (SCI) (163). Inactive mTOR dephosphorylates TFEB to promote the expression of autophagy-related genes and elevated autophagic flux results in the decline of RIPKs and MLKL, which inhibits necroptosis and facilitates the neurofunction restoration (163). However, another study about SCI yielded the opposite conclusion that autophagy may deteriorate the necroptosis-mediated injury because rapamycin antagonizes the edaravone-induced downregulation of phosphorylated necroptotic proteins through autophagy (164). The discrepancy probably derives from different cell types because neurons are the focus in the former, while human brain microvascular endothelial cells are targeted in the latter. Therefore, the effect of autophagy on necroptosis seems to be context-dependent and cell-type specific.

mTORC1 regulates ubiquitin-dependent RIPK3 degradation through autophagy. Yadong Xie and his colleagues found that mTOR hyperactivated by the Western diet or TSC1 knockout caused substantial RIPK3 accumulation through the blockade of autophagy in intestinal epithelial cells, and p62 was involved in the autophagic degradation of RIPK3 as a specific recognizer for ubiquitinated cargo (11). TRIM11, an E3 ubiquitin ligase, catalyzes polyubiquitination of RIPK3 for autophagic degradation, which was abrogated by mTORC1 overexpression (11). Consequently, this study revealed two mechanisms by which mTOR upregulates necroptosis in an autophagy-dependent manner. Kevin Bray et al. (165) also verified that mTOR inhibits the autophagic degradation of ubiquitinated RIPK3 and interferes with TRIM11 to hinder RIPK3 ubiquitination modification to protect RIPK3 from p62-mediated autophagic degradation.

Mitophagy, another vital subtype of autophagy, has been demonstrated to be involved in necroptosis. Especially the damaged mitochondria are the main site of ROS production, which is closely associated with necroptosis. Mitophagy can eliminate injured or fragmentized mitochondria to restrain the production of ROS, thereby preventing necroptosis. Bo Xu et al. revealed that exosomes produced from Schwann cells induced AMPK-mediated mitophagy to subdue the generation of ROS and alleviate necroptosis in PC12 cells but failed to explore the role of mTORC1 in the mechanisms related to mitophagy and necroptosis despite the close relationship between AMPK and mTORC1 (166). Mitochondrial permeability transition pore opening, ROS production, and mitochondrial fission are considered mediators of necroptosis evidence by phosphorylated MLKL locating mitochondrial fractions, which can be alleviated by rapamycin through mitophagy-dependent removal of impaired mitochondria (167, 168). A recent study found that a triggering receptor expressed on myeloid cells-1 (TREM-1) induced necroptosis in macrophages by activating mTOR. The study further concluded that mTOR could elevate the expression levels of mitochondrial fission process protein 1 (MTFP) and phosphatase phosphoglycerate mutase family member 5 (PGAM5) to activate dynamin-related protein 1 (DRP1)-mediated mitochondria fission and subsequent mitophagy (169). Despite the limited evidence for this recently identified pathway, it remains a plausible mechanism by which mTOR regulates necroptosis in a mitophagy-dependent manner.

Nevertheless, there is more than one signaling pathway that connects mitophagy and necroptosis, and mitophagy may potentially serve a pro-necroptotic effect via certain mechanisms rather than an anti-necroptotic role. For instance, Sorafenib has been found to induce mitophagy through the mTORC1-TFEB pathway, and mitophagy-mediated MFN degradation contributed to the increased expression of MAM constituents and induced excessive contact between mitochondria and the ER, an intracellular calcium pool. The process mentioned above resulted in Ca²⁺ flow from the ER to the mitochondria, and this Ca²⁺ overload triggered necroptosis (170).

The key molecules that play a crucial role in necroptosis are directly regulated by mTOR (Figure 3). The kinase activity of mTORC1 is effectively utilized to phosphorylate RIPK1, activating RIPK1 and subsequent regulation of necroptosis. Abe et al. observed that rapamycin, an mTOR inhibitor, exhibited a protective effect on cardiomyocytes against necroptosis induced by TNFα/z-VAD-fmk (zVAD) (171). Subsequent investigations have indicated that mTORC1 selectively phosphorylates different RIPK1 sites (e.g., Ser166 and Ser320) and that phosphorylation of these two sites is positively and negatively correlated with RIPK1 activity, respectively (171). Rapamycin promoted the phosphorylation at Ser320 and decreased phosphorylation at Ser166, thereby impairing the activity of RIPK1. Given that Ser320 is required for the reciprocal interaction between RIPK1 and RIPK3, phosphorylation of Ser320 induced by mTOR inhibitor hindered the RIPK1-RIPK3 connection (171). Consequently, mTORC1 facilitates necroptosis by regulating RIPK1 activity and the interaction between RIPK1 and RIPK3 through phosphorylation.

As AMPK has a well-established role as a mTORC1 inhibitor, RIPK1 phosphorylation by AMPK has been increasingly recognized. Tao Zhang et al. uncovered that AMPK stimulated by glucose deprivation restricts RIPK1 activation by phosphorylating RIPK1 S415, thereby inhibiting necroptosis during short-term energy stress (172). Prolonged 2-DG treatment to mimic long-term glucose starvation leads to a decrease and an increase in p-RIPK1 at Ser⁴¹⁵ and Ser¹⁶⁶, respectively, which implies that AMPK mediates the conversion from cellular protection to necroptosis by regulating RIPK1 phosphorylation at different sites in the context of glucose deficiency (172). However, another study reported that activated AMPK inhibits necroptosis through the enhancement of pro-caspase 8 stability, rather than regulating the level of p-RIPK1 in acute pancreatitis mice models (173). The divergent conclusions mentioned above can be attributed to the different activators of AMPK and the cell types. Different metabolic status leads to diverse types of cell death in different cells. Consequently, it is necessary and meaningful to investigate the relationship between metabolic status and necroptosis and the connections between AMPK and RIPK1 in necroptosis.

It is widely recognized that TNFα is a crucial signal that initiates necroptosis. Consequently, mTOR also targets necroptosis to modulate it. It was demonstrated that TNFα/z-VAD-fmk (zVAD)-induced necroptosis was significantly suppressed by a PI3K/mTOR inhibitor or miRNA-mediated mTOR gene silencing (174). An increase in TNFα mRNA was detected in the cells undergoing necroptosis, suggesting that necroptosis was accompanied by a significant rise in TNFα synthesis and secretion. To elucidate the inherent relationship between mTOR and TNFα, researchers used a combination of PI3K/mTORC1 inhibitor and miRNA knockdown of mTOR or AKT. Their findings revealed that TNFα mRNA was significantly decreased in the absence of mTOR, which indicated that PI3K/AKT/mTORC1 could upregulate the synthesis of TNFα (174). c-Jun N-terminal kinase (JNK) is involved in TNFα synthesis and autocrine and is a downstream effector of mTOR to regulate necroptosis (175–177). McNamara et al. found that the level of active JNK relevant to necroptosis increased in cells where AKT/mTOR was suppressed by siRNA knockdown or inhibitors. This finding suggested that TNFα autocrine was promoted through AKT/mTOR/JNK to exacerbate the necroptosis and establish a positive feedback loop (174). In addition to TNFα, it is noteworthy that TRAIL, another necroptosis inducer, may be associated with TSC2 and mTOR. A recent study revealed that TSC2 facilitates the mTORC2-skewed profile in malignant cells to defend against the attack from cytotoxic T cells. TSC2 ablation leads to mTORC1 overactivation and increased expression of TRAIL receptor to increase the susceptibility to necroptosis, indicating the close relationship between TSC2-mTOR and TRAIL signaling and their pivotal role in necroptosis (178).

Moreover, it’s conceivable that mTORC1 is also regulated by necroptosis-related molecules. Rune Busk Damgaard et al. used hepatocyte-specific knockout of OTULIN (Otulin^Δhep) mice to establish that the lack of OTULIN led to mTORC1-associated steatohepatitis, hepatic fibrosis, and cancer (179). Abnormal mTORC1 activation was indicated in Otulin^Δhep mice, and the administration of the mTORC1 inhibitor Rapamycin alleviated the liver injury and pathology caused by OTULIN insufficiency, which might be associated with TSC and RHEB. However, the intrinsic mechanism by which OTULIN regulates mTORC1 and its contribution to necroptosis still requires further research.

ROS is regarded as a signal of necroptosis (180–182). Mechanically, RIPK1 autophosphorylation and activation are promoted by ROS, which facilitates the recruitment of RIPK3 and the assembly of necrosomes. Thus, oxidative stress connects mTOR to necroptosis through ROS (Figure 3).

mTOR regulates the generation of ROS. Q Liu et al. revealed that the pharmacological or genetic blockade of AKT/mTOR undermined the production of ROS without affecting the interaction between RIPK1 and RIPK3 in HT22 cells treated with TNFα/zVAD to alleviate necroptosis, indicating that AKT/mTOR functioned downstream of RIPK1 but upstream of ROS generation (183). Forkhead box subclass O (FOXO) transcription factors, which govern antioxidant defenses, were substantiated to be involved in the regulatory mechanism of AKT/mTOR regarding redox reaction and oxidative stress (183, 184). FOXO phosphorylated by AKT is deprived of pro-transcription capacity and is removed from the nucleus when the 14-3-3 protein binds to it (185). Sustained AKT/mTOR inhibition relieved the phosphorylation suppression of FOXO and facilitated antioxidant response to downregulate necroptosis (183). Since AKT has been widely acknowledged as an upstream inhibitor of FOXO, mTOR, a downstream molecule of AKT, still warrants further exploration for its relationship with FOXO and potential regulatory mechanism.

Nuclear factor-erythroid 2-related factor 2 (Nrf2) is another target of mTOR to regulate oxidative stress. Similar to FOXO, Nrf2 is another transcription factor that controls the expression of antioxidant genes. Kelch-like ECH-associated protein 1 (Keap1), a ubiquitin ligase complex, binds to Nrf2 to facilitate its degradation by ubiquitination. p62 has an affinity for Keap1 and is therefore considered a guardian of Nrf2. Keap1 is inhibited upon binding to p62, facilitating the release and stabilization of Nrf2 for translocation to the nucleus and subsequent antioxidant response (186, 187). It has been revealed that the mTOR inhibitor CCI-779 facilitated the dissociation of Nrf2 from Keap1 by upregulating p62 to enhance the antioxidant reaction but blocked the nuclear translocation of Nrf2 to prohibit antioxidant defense (165).

Intriguingly, the pro-necroptotic and anti-necroptotic roles of mTOR were well illustrated in this study (165). In contrast to the views of the majority of the studies above, this study concluded that the mTOR inhibitor-induced necroptosis through different mechanisms. However, it is not contradictory because the regulatory network between mTOR and necroptosis is complicated by the intersection of numerous signaling pathways. The positive or negative regulatory effect of mTOR on necroptosis is determined by the predominant mechanism, which may be influenced by various factors, including cell type and stimulus. Kevin Bray et al. demonstrated that the effect of mTOR inhibitors blocking the nuclear translocation of Nrf2 was more significant than inducing mitophagy to eliminate ROS and relieving Nrf2 from Keap1, which was ultimately manifested as the promotional role of mTOR inhibitors on necroptosis (165).

Necroptosis considered a proinflammatory cell death, has been authenticated to be associated with a variety of diseases. We will discuss potential implications in immune-related disorders and infectious diseases by mTOR through necroptosis regulation, such as autoimmune disease, sepsis and related complications, graft rejection, and infection (131, 188–190).

The AKT/mTOR pathway promotes TNFα-induced necroptosis by increasing TNFα production and activating JNK, both of which facilitate TNFα autocrine and deteriorate the damage caused by necroptosis (174). The finding that mTOR regulates necroptosis through TNFα implies that the blockade of the signaling pathway could be a potential direction in suppressing pathologic inflammation and consequently alleviate the inflammatory injury, which is particularly beneficial in treating acute pancreatitis, bacterial infections and systemic inflammatory response syndrome (SIRS). Zhong et al. identified a novel mechanism by which mTORC1 promoted DRP1-mediated mitochondrial fission through downstream molecules, PGAM5 and MTFP, thereby aggravating the inflammatory damage induced by necroptosis in alveolar macrophages treated with LPS, indicating a new therapeutic target for LPS-triggered acute lung injury (169).

The pathogenesis of IBDs, including Crohn’s disease and ulcerative colitis, is related to the necroptosis of intestinal epithelial cells, a process in which mTOR has been identified as a participant. Xie et al. revealed that mTOR overactivation promoted necroptosis of epithelial cells to damage the intestinal barrier and induce intestinal inflammation and inflammation-related cancer (11). Mechanically, mTOR inhibited autophagic degradation of RIPK3 by downregulating RIPK3 ubiquitination to promote necroptosis, which provided more precise therapeutic directions for IBDs (11). Moreover, the role of necroptosis in other autoimmune diseases has been validated, including autoimmune hepatitis, lupus nephritis, and autoimmune lymphoproliferative syndrome (191–194). However, investigations into the potential therapeutic value of mTOR in the aforementioned autoimmune disorders through necroptosis are lacking.

It has been demonstrated that mTOR plays a role in immune defense against pathogens by regulating necroptosis, which provides a possible target for treating infectious diseases. Macrophages infected with Candida albicans, a common fungal pathogen, undergo MLKL-mediated necroptosis considerably. mTORC1 contributes to the activation of RIPK1, RIPK3, and MLKL and specific knockout of Tsc1 in macrophage/neutrophil gives rise to the prominent increase in fungal burden and cell death, suggesting the potential of TSC1-mTORC1 in defending pathogen infections (195). Moreover, AKT/mTOR is inhibited by ursolic acid to promote autophagy and suppress the necroptosis of macrophages, enhancing the anti-infection effect against Mycobacterium tuberculosis (196). Nevertheless, further studies are required to validate the role of mTOR-regulated necroptosis in other pathogen infections, such as SARS-CoV-2.

In terms of graft rejection, substantial evidence proves the function of necroptosis in organ transplantation (190, 197–199). However, only one study observed that the cardiac allograft models survived longer with the treatment of mTOR inhibitor sirolimus, which may be associated with necroptosis (190). Therefore, more research is in demand to explore whether and how mTOR is engaged in regulating necroptosis in graft rejection.

The regulatory mechanism of mTOR on necroptosis benefits the treatment of various tumors. It has been verified that auranofin can induce necroptosis by inhibiting the PI3K/AKT/mTOR pathway to restrain the exacerbation of non-small cell lung cancer (NSCLC); however, additional research is needed to elucidate the underlying mechanism (200). In lung cancer, the combination administration of 11-MT and an autophagy inhibitor exhibited more efficient therapeutic benefits compared to 11-MT used alone. This can be attributed to the finding that the AMPK/mTOR pathway inhibited the interaction between RIPK1 and RIPK3 via autophagy, suppressing necroptosis (161). Moreover, the therapeutic value of regulating necroptosis via mTOR has also been confirmed in schwannoma. Necroptosis of schwannoma cells is induced by LiCl through the AKT-mTOR-p70S6K axis to restrain the deterioration of schwannoma (201).

Regarding urinary tumors, the role of mTOR in regulating necroptosis has been gradually realized. Jin et al. used GNE-493 to reveal a new therapeutic target for prostate cancer by blocking the PI3K-AKT-mTOR pathway and inducing ROS production which brought about oxidative damage and necroptosis in prostate cancer cells (202). In renal cell carcinoma, an mTOR inhibitor has been demonstrated to promote autophagy-mediated RIPK clearance to inhibit necroptosis, but it also exerts a positive role in necroptosis by suppressing Nrf2 nuclear translocation and consequent antioxidant defense. Therefore, autophagy inhibitors are expected to enhance the efficacy of mTOR inhibitors in treating renal cell cancer (165).

There are numerous poisonous agents. For instance, Sorafenib is a targeted drug for hepatocellular carcinoma but is restricted in its clinical applicability due to its myocardial toxicity to some extent (203, 204). mTOR can be targeted to protect the myocardium from Sorafenib, which was validated to degrade MFN2 through mTOR-regulated mitophagy, disrupting the balance of mitochondrial Ca²⁺ and inducing necroptosis (170). Therefore, mTOR represents a potentially effective treatment for myocardial damage induced by Sorafenib. Additionally, saturated fatty acids can trigger necroptosis in cardiomyocytes to provoke oxidative damage (205). Mingyue Zhao et al. found that the AKT/mTOR signaling pathway activated by palmitic acid elevated the levels of RIPK1 and RIPK to induce the necroptosis of cardiomyocytes, which is likely to induce myocardial hypertrophy. They concluded that mTOR inhibition could reverse necroptosis triggered by increased saturated fatty acid to treat myocardial hypertrophy (206).

Despite most studies holding the view that mTOR is indispensable in promoting necroptosis, a few studies have reached the opposite conclusion. Intake of the plastic degradation product microplastic (MP) and plastic additive Di (2-ethylhexyl) phthalate (DEHP) can elicit the toxicity of skeletal muscle. Liu et al. investigated its potential mechanisms and proposed that DEHP/MP triggered necroptosis by inhibiting the PI3K/AKT/mTOR signaling pathway and stimulating oxidative stress, which suggested that mTOR could be targeted to curtail the plastic-induced muscle toxicity (207).

An increasing number of studies have substantiated the role of necroptosis in neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Multiple Sclerosis, and amyotrophic lateral sclerosis (ALS) (208–211). However, explorations into the therapeutic utility of mTOR-regulated necroptosis in these disorders are lacking. Indirect evidence indicates the treatment potential to some extent. p62 is involved in the TNFα-induced necroptosis by interacting with RIPK1 in AD, which is aggravated by comprised autophagy through aberrant p62 accumulation (212). As a well-established autophagy inhibitor, mTOR is likely to regulate necroptosis through the autophagy-p62-RIPK1 axis and serve as a potential therapeutic target in AD. A recent study found that the activation of necroptosis by the long noncoding RNA MEG3 is associated with AD (213). The strong correlation between MEG3 and mTOR activity has been established in numerous diseases, including neuroblastoma, endometrial carcinoma, and cisplatin-induced nephrotoxicity (214–217). Thus, mTOR may mediate MEG3-induced necroptosis. Due to the lack of direct evidence, further investigations are urgently required.

In other neurological diseases, a study revealed that AKT/mTOR contributed to ROS production to exacerbate necroptosis in the mouse hippocampal neuronal cell line HT-22. However, the study did not delve deeper into the potential involvement of this mechanism in neurological diseases through in vivo experiments (183). Ying Wang et al. revealed the treatment mechanisms of LiCl in schwannoma by activating AKT/mTOR axis to induce necroptosis (201).

Despite preclinical experiments confirming the role of mTOR inhibitors in a variety of diseases, most clinical trials focus on their application in organ transplant as a potent immunosuppressant. In terms of graft-versus-host disease (GVHD) prophylaxis, the addition of sirolimus to standard therapy is propitious to reducing the incidence and severity of graft-versus-host disease (GVHD) and improving the life quality in kidney transplant recipients (241, 242, 254, 255). Additionally, everolimus improves the prognosis of liver or heart transplants with fewer adverse effects (256, 257). Since the use of immunosuppressant increases the susceptibility to infections, whether the administration of mTOR inhibitors influence infections has been paid attention to in organ transplant. Tedesco-Silva, H. et al. compared the efficacy of everolimus and low-dose calcineurin inhibitor with standard therapy (calcineurin inhibitor and mycophenolic acid) and found that the incidence of cytomegalovirus (CMV) infection decreased significantly in patients treated with everolimus (258). Moreover, sirolimus also prevents CMV recurrence in CMV-positive kidney transplant recipients (259). Hence, mTOR inhibitor is an effective and safe therapeutic strategy in organ transplant.

The value of mTOR inhibitors in antitumor therapy has been investigated, especially in urinary tumors. A phase II clinical trial confirmed that combining cyclophosphamide and everolimus leads to the depletion of Tregs and myeloid-derived suppressor cells, which improves the survival of metastatic renal cell cancer (RCC) patients (260). Another phase 2 study proved that the combination of lapatinib plus everolimus is effective in restricting the expansion of tumors with controllable side effects in non-clear cell RCC (261). However, the effectiveness of mTOR inhibitors in treating RCC remains controversial. A phase 3 trial exhibited a longer recurrence-free survival in patients receiving everolimus than those treated with placebo but the result failed to meet the statistical requirement and support the adjuvant treatment of everolimus for RCC (225). Other regimens display improved therapeutic efficacy over mTOR inhibitors in RCC. Lenvatinib plus pembrolizumab prolonged the progression-free and overall survival and improved health-related quality-of-life in patients with advanced RCC compared with Lenvatinib plus everolimus (223, 262). In addition to RCC, the immunomodulatory effect of mTOR inhibitors has been employed in the treatment of bladder cancer. The count of γδT cells specific to BCG and the production of cytokines are boosted by rapamycin, suggesting that rapamycin is a potential adjuvant agent of bladder cancer by enhancing the immune response to BCG to exert antitumor effect (230).

Moreover, the application of mTOR inhibitors has been investigated extensively in breast cancer and other tumors, but few researchers have reached a supportive or positive conclusion. Triple treatment composed of ribociclib, everolimus, and endocrine therapy shows a clinical benefit with manageable safety profile in advanced breast cancer (263). Everolimus plus letrozole or exemestane benefits the outcome and has lower adverse effects in postmenopausal advanced breast cancer patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (226, 264). Nonetheless, several clinical trials refute the therapeutic efficacy of everolimus in survival improvement in breast cancer (229, 265, 266). A randomized phase II trial demonstrated that the treatment of everolimus and letrozole prolonged the progression-free survival in recurrent endometrial carcinoma (267). Inhibiting PI3K/AKT by everolimus or temsirolimus is tolerable and beneficial to overall survival in glioma and glioblastoma patients (233, 268).

mTOR inhibitor is a promising therapeutic target for autoimmune diseases. Sirolimus downregulates the indicators of disease activity and elevates Tregs in patients with rheumatoid arthritis more significantly than conventional therapy (251). Over half of patients with connective tissue disease-related thrombocytopenia (CTD-TP) who received oral sirolimus administration achieved complete remission, suggesting that sirolimus is an alternative in treating CTD-TP (250). Similarly, sirolimus increases the count of platelets in pediatric chronic immune thrombocytopenia (249).

Furthermore, mTOR inhibitors can also be used as adjuvant agents to augment the efficacy of conventional drugs in treating tuberculosis. Researchers evaluated the lung function and sputum culture to compare the efficacy of different adjuvants plus standard tuberculosis treatment, concluding that everolimus is a potential adjuvant in tuberculosis therapy with safety and well-tolerance (245). In terms of respiratory diseases, the treatment of sirolimus contributes to a significant decrease in circulating fibrocytes to alleviate lung fibrosis, which implies the effect of sirolimus on treating idiopathic pulmonary fibrosis (244).

Regarding neurological disorders, mTOR is a promising therapeutic target as well. Patients of ALS receiving rapamycin underwent a decline in proinflammatory cytokines and an increase in Tregs to inhibit aberrant neuroinflammation (246).