Necroptosis is a programmed form of inflammatory necrotic cell death that shares morphological features with accidental necrosis — cell swelling, organelle dysfunction, and membrane rupture — but is executed through a well-defined signaling cascade involving receptor-interacting protein kinases (RIPKs) and mixed lineage kinase domain-like (MLKL) pseudokinase. [1] Unlike apoptosis, which is an immunologically silent or even anti-inflammatory form of cell death, necroptosis is inherently pro-inflammatory: the loss of plasma membrane integrity releases intracellular damage-associated molecular patterns (DAMPs) that activate surrounding immune cells, amplify neuroinflammation, and propagate the cycle of neuronal death in neurodegenerative disease. [2]
Necroptosis is increasingly recognized as a significant contributor to the neuronal loss observed in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), and stroke. [3] The evidence is both histopathological (detection of necroptosis markers in post-mortem brain tissue) and experimental (genetic or pharmacological inhibition of the pathway protects neurons in cellular and animal models). Critically, necroptosis can be triggered by the same protein aggregates that define these diseases — amyloid-beta (Aβ), tau, and alpha-synuclein (αSyn) — linking proteostasis failure directly to programmed necrotic death. [4]
The therapeutic targeting of necroptosis represents a promising strategy for neurodegenerative disease modification because the pathway is druggable (multiple kinase inhibitors exist), the key executioner MLKL is not required for normal development (unlike essential apoptotic caspases), and pharmacological inhibition is effective even after the necroptotic signal has been initiated. [5]
The canonical necroptosis pathway is initiated by activation of death receptors (TNF-R1, Fas, TRAIL-R) or Toll-like receptors (TLR3, TLR4) under conditions where execution of apoptosis is blocked (e.g., by caspase-8 inhibitors, caspase-8 deficiency, or viral immune evasion proteins). [6] The pathway proceeds through three sequential steps: activation of RIPK1, activation of RIPK3, and activation of MLKL.
RIPK1 activation: Upon engagement of death receptors by their ligands (TNF-α, Fas ligand, TRAIL), a complex forms at the intracellular death domain of the receptor — the "complex I" consisting of RIPK1, TRADD, TRAF2/5, and cIAP1/2. Under survival conditions, this complex activates NF-κB and cell survival pathways. Under pro-necroptotic conditions, deubiquitination of RIPK1 (by CYLD or A20) converts complex I to a "complex IIa" (also called the ripoptosome) containing RIPK1, FADD, and procaspase-8. When caspase-8 activity is low or inhibited, RIPK1 remains active and recruits RIPK3. [7]
RIPK3 activation: RIPK3 is recruited to the RIPK1-containing complex through interaction of their RIP homotypic interaction motifs (RHIMs). RIPK3 then undergoes autophosphorylation, with key activation sites including S227 (human) and S232/S227 (mouse). Activated RIPK3 forms a high-molecular-weight signaling complex called the necrosome. The necrosome can also form independently of RIPK1 through alternative RHIM-mediated interactions with sensors like ZBP1 (Z-DNA binding protein 1, also called DAI), which detects viral nucleic acids and endogenous retroelements. [8]
MLKL activation: The key downstream effector of RIPK3 is MLKL. MLKL contains an N-terminal four-helix bundle (4HB) domain that binds membrane lipids and disrupts membrane integrity, and a C-terminal pseudokinase domain (KBD) that interacts with RIPK3. RIPK3 phosphorylates MLKL at S357 and S358 (mouse), causing a conformational change that releases the 4HB domain and enables MLKL oligomerization. [9] MLKL oligomers (typically trimers or tetramers) translocate to the plasma membrane, where they bind phosphatidylinositol phosphates (PIP2, PIP3) and cardiolipin, creating pores that disrupt membrane integrity. Membrane rupture releases cellular contents, including HMGB1, ATP, mitochondrial DNA, and S100 proteins — all potent DAMPs that activate immune cells.
While the TNF-R1-initiated RIPK1-RIPK3-MLKL pathway is the best characterized, necroptosis can also be triggered through RIPK1-independent and MLKL-independent mechanisms. [6:1]
ZBP1-dependent necroptosis: ZBP1 (DAI/DLM1) is a cytosolic DNA sensor that contains two RHIM domains and can directly recruit RIPK3 independently of RIPK1. This pathway is activated by herpesvirus infections and by endogenous nucleic acid species, including the Z-RNA structures formed by endogenous retroelements. In neurodegeneration, ZBP1-mediated necroptosis may be triggered by cytoplasmic nucleic acid accumulation, a feature of some polyglutamine diseases and C9orf72-linked ALS/FTD.
TLR3/TLR4-TRIF pathway: Engagement of TLR3 (by double-stranded RNA) or TLR4 (by LPS in the presence of caspase-8 inhibition) recruits the adaptor TRIF, which contains a RHIM domain and can directly activate RIPK3. This pathway is primarily studied in immune cells but may also operate in neurons and glia.
RIPK3-MLKL independent: Some forms of programmed necrosis proceed through RIPK3 activation without MLKL involvement, or through completely caspase-independent mechanisms involving lysosomal rupture (called "ferroptosis" when iron-dependent). The interplay between necroptosis and ferroptosis is particularly relevant in neurodegeneration, where iron accumulation is a common feature.
The necroptosis pathway is subject to multi-layered regulation that determines whether a cell dies by necroptosis or survives. [6:2]
Caspase-8: The most critical regulator is caspase-8, which directly cleaves and inactivates both RIPK1 and RIPK3. Caspase-8 also cleaves the pseudokinase RIPK2 to prevent its association with RIPK3. When caspase-8 is absent or inhibited (genetically, pharmacologically, or by viral proteins), the RIPK1-RIPK3-MLKL pathway proceeds unchecked.
Ubiquitination: cIAP1/2 and linear ubiquitin chain assembly complex (LUBAC) add ubiquitin chains to RIPK1, targeting it for proteasomal degradation or directing it toward NF-κB activation. Deubiquitinating enzymes (DUBs) — CYLD, A20 (TNFAIP3), and USP21 — remove these chains, promoting necrosome formation.
Phosphorylation: RIPK1 is phosphorylated at multiple sites (S14, S166, S320) that modulate its kinase activity and interactions. RIPK3 autophosphorylation at S227 is essential for MLKL recruitment. Protein phosphatases (PP1, PPM1B) can dephosphorylate these sites, attenuating the pathway.
Metabolic regulation: The necroptosis pathway is energetically demanding — ATP is required for RIPK3 autophosphorylation and MLKL oligomerization. Metabolic stress (low ATP, high AMPK activation) can modulate necroptosis sensitivity. This has implications for neurodegeneration, where neuronal metabolism is frequently impaired.
Multiple studies have detected necroptosis markers in the AD brain, including phosphorylated MLKL (p-MLKL), active RIPK3, and elevated MLKL mRNA and protein. [3:1] p-MLKL immunoreactivity is observed in neurons in the prefrontal cortex, hippocampus, and entorhinal cortex — regions that are preferentially affected by AD pathology. Importantly, p-MLKL staining co-localizes with hyperphosphorylated tau in neurons containing neurofibrillary tangles, suggesting that tau pathology and necroptosis occur in the same cellular populations.
RIPK3 expression is elevated in AD brain tissue, particularly in microglia and astrocytes as well as neurons. [10] The source of this elevation appears to be both increased transcription (driven by NF-κB activation in response to chronic neuroinflammation) and reduced degradation. RIPK1 is also upregulated in AD brains, and higher RIPK1 levels correlate with greater cognitive impairment at time of death.
The protein aggregates that define AD — Aβ plaques and hyperphosphorylated tau tangles — directly trigger necroptotic signaling through multiple mechanisms. [11]
Aβ-induced necroptosis: Soluble Aβ oligomers (the most synaptotoxic species) activate necroptosis in cultured neurons and in mouse models of AD. Aβ oligomers bind to multiple neuronal surface receptors (PrP^C, RAGE, LRP1) that activate downstream pro-inflammatory and pro-death signaling cascades. In the presence of caspase-8 inhibition (which can occur due to chronic low-level activation), Aβ-induced RIPK1 activation progresses to necroptosis. Aβ also induces ZBP1 expression in neurons, providing an RIPK1-independent trigger for necroptosis.
In 5xFAD and APP/PS1 mouse models, genetic deletion of RIPK3 or MLKL, or pharmacological inhibition of RIPK1 with necrostatin-1, reduces neuronal death, improves cognitive performance, and decreases markers of neuroinflammation. [3:2] These findings strongly implicate necroptosis as a downstream executor of Aβ toxicity.
Tau-driven necroptosis: Hyperphosphorylated tau itself contributes to necroptotic sensitivity. Tau physically interacts with RIPK1 and RIPK3 in neurons, potentially facilitating necrosome formation. In tau-transgenic mice (rTg4510, PS19), inhibition of necroptosis signaling (RIPK3 KO, MLKL KO, or necrostatin-1 treatment) reduces neuronal loss and slows disease progression, even without reducing tau pathology itself. [12]
This suggests a model in which tau pathology primes neurons for necroptotic death — perhaps by disrupting the cytoskeletal architecture that normally separates RIPK3 and MLKL, or by providing a scaffold for necrosome assembly — while Aβ and neuroinflammation provide the trigger.
Necroptosis and neuroinflammation form a vicious cycle in AD. [3:3] Neuronal necroptosis releases DAMPs (HMGB1, ATP, mitochondrial DNA) that activate surrounding microglia and astrocytes through pattern recognition receptors (TLRs, NLRP3 inflammasome). Activated glia then release cytokines (TNF-α, IL-1β, IL-6) that further activate RIPK1 in neighboring neurons through death receptor engagement. This creates a propagating wave of inflammatory neuronal death that spreads through the cortex and hippocampus.
Microglia themselves can undergo necroptosis in response to chronic activation by Aβ and tau, producing a source of pro-inflammatory cytokines that amplifies the cycle. The concept of "inflammatory necroptosis" in glia is particularly relevant for AD, where widespread microglial activation is a hallmark feature.
Multiple strategies for inhibiting necroptosis in AD are under investigation. [10:1] Necrostatin-1 (Nec-1) and its improved derivatives (Nec-1s, 7-Cl-O-Nec) are allosteric inhibitors of RIPK1 kinase activity that cross the blood-brain barrier. In AD mouse models, Nec-1 reduces neuronal loss, improves spatial memory (Morris water maze), and reduces neuroinflammation. However, Nec-1 has modest potency and metabolic instability, driving the development of improved compounds.
RIPK1 inhibitors in clinical development: Daprodustat (GSK1070806) is a RIPK1 inhibitor originally developed for inflammatory diseases that has shown neuroprotective effects in AD models. RR-1042 and Zharp-1 are more selective next-generation RIPK1 inhibitors with improved pharmacokinetics. RIPA-56 is an orally bioavailable RIPK1 inhibitor that reduced neuronal death and cognitive deficits in 5xFAD mice.
RIPK3 and MLKL inhibitors: RIPK3 is considered a less attractive drug target than RIPK1 because its kinase activity is not as easily druggable and because RIPK3 deletion in mice causes unexpected immunological phenotypes. However, functional inhibitors of RIPK3 (decoy peptides, dominant-negative mutants) and MLKL (phosphorylation site mutants, oligomerization blockers) are being explored. The most advanced approach targets RIPK1 upstream, preventing recruitment of both RIPK3 and caspase-8 pathways.
Combination with anti-amyloid and anti-tau therapies: Necroptosis inhibitors are most likely to be useful as adjuncts to disease-modifying therapies that reduce the upstream triggers (Aβ, tau). Reducing the load of pathological proteins should decrease the demand on necroptosis inhibition, while necroptosis inhibition should protect neurons that still bear residual pathology.
In Parkinson's disease, necroptosis is implicated in the death of dopaminergic neurons in the substantia nigra pars compacta (SNc), both in toxin-based models (MPTP, 6-OHDA, rotenone) and in alpha-synuclein-based models. [13] Post-mortem studies of PD patient brains show elevated RIPK1, RIPK3, and p-MLKL in the SNc and in the striatum, with the highest levels observed in neurons with alpha-synuclein inclusions.
MPTP model: In the MPTP mouse model of PD, RIPK3 and MLKL are activated in dopaminergic neurons during the acute toxic phase. Genetic deletion of RIPK3 or MLKL, or treatment with necrostatin-1, provides significant neuroprotection and preserves dopaminergic terminals in the striatum. Notably, MPTP-induced Parkinsonian symptoms are markedly attenuated in RIPK3-KO mice.
6-OHDA model: Unilateral 6-OHDA lesion of the medial forebrain bundle causes progressive loss of dopaminergic neurons. Necrostatin-1 treatment at the time of lesion significantly reduces neuronal loss and preserves motor function, as measured by apomorphine-induced rotation and cylinder test performance.
Alpha-synuclein models: Pre-formed alpha-synuclein fibrils (PFFs) injected into the mouse striatum trigger progressive alpha-synuclein pathology that spreads from the striatum to the SNc. RIPK3 and MLKL are activated in neurons containing phosphorylated alpha-synuclein inclusions, and inhibition of necroptosis (genetic or pharmacological) reduces both neuronal death and the spread of alpha-synuclein pathology. [13:1]
Alpha-synuclein promotes necroptotic death through several mechanisms. [13:2] First, αSyn aggregates activate the unfolded protein response (UPR) in the endoplasmic reticulum, which includes PERK-mediated phosphorylation of eIF2α. PERK activation potentiates necroptosis signaling by phosphorylating RIPK1 and facilitating necrosome formation. Second, αSyn fibrils can be taken up by neurons through endocytosis, and the process of endosomal rupture (triggered by the fibrils' ability to perforate membranes) activates caspase-8 inhibition, pushing the cell toward necroptosis. Third, αSyn interacts with the mitochondrial protein TOM20, impairing mitochondrial function and increasing reactive oxygen species (ROS) production. ROS activate the NF-κB pathway, upregulating RIPK1 and RIPK3 expression, and directly oxidize components of the necrosome.
A key intersection between PD pathophysiology and necroptosis is the autophagy-lysosome pathway. Loss-of-function mutations in PINK1 and PRKN/Parkin (causing autosomal recessive PD) impair mitophagy and lead to accumulation of damaged mitochondria. Damaged mitochondria release mitochondrial DNA and formyl peptides that activate the NLRP3 inflammasome and RIPK1-dependent necroptosis. In PINK1-deficient neurons, treatment with necroptosis inhibitors blocks the death triggered by mitochondrial toxins, suggesting that necroptosis is the executioner of mitochondrial dysfunction in PD.
In ALS, necroptosis contributes to motor neuron death, particularly in SOD1, TDP-43, and FUS models. [4:1] RIPK1 and RIPK3 are activated in spinal cord motor neurons in ALS patients and in G93A-SOD1 mice. Necrostatin-1 treatment delays disease onset and extends survival in SOD1 mice. The inflammatory environment created by activated astrocytes and microglia in ALS provides the TNF-α and other cytokines that trigger RIPK1 activation in motor neurons.
Necroptosis is strongly activated in acute CNS injury and contributes significantly to secondary neuronal loss. [14] In ischemic stroke, oxygen-glucose deprivation (OGD) activates RIPK1, RIPK3, and MLKL in neurons within the ischemic core and penumbra. The inflammatory DAMPs released by necroptotic cells exacerbate the neuroinflammatory response and contribute to blood-brain barrier breakdown. Necrostatin-1 administered after the ischemic event (within a therapeutic window) reduces infarct volume and improves functional recovery in rodent stroke models. In TBI, the mechanical injury triggers necroptosis in a subset of neurons, and the subsequent inflammatory response contributes to progressive secondary injury. RIPK1 inhibitors given after experimental TBI reduce neuronal loss and improve behavioral outcomes.
In Huntington's disease, mutant huntingtin (mHTT) protein aggregation promotes necroptotic signaling through the ZBP1 pathway. [15] mHTT activates the UPR and impairs protein quality control systems, creating conditions that favor necrosome formation. RIPK1, RIPK3, and MLKL are elevated in the striatum of HD patients and in mouse models (R6/1, Q140). Necrostatin-1 treatment reduces neuronal loss in striatal cultures treated with mutant huntingtin fragments and in Drosophila models of HD.
In multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), oligodendrocytes are primary targets of necroptosis. RIPK3 and MLKL are activated in oligodendrocytes in MS lesions, and genetic deletion of RIPK3 or MLKL strongly protects against EAE. [15:1] This suggests that necroptosis of oligodendrocytes contributes to demyelination and disease progression in MS.
When neurons undergo necroptosis, the loss of plasma membrane integrity releases a constellation of intracellular molecules that function as damage-associated molecular patterns (DAMPs). [16]
HMGB1 (high mobility group box 1): The most abundant DAMP in neurons, HMGB1 is released passively upon membrane rupture and actively through deacetylation in stressed cells. HMGB1 binds to RAGE and TLR2/4 on microglia and astrocytes, activating NF-κB and the NLRP3 inflammasome, and promoting pro-inflammatory cytokine release. In the brain, HMGB1 contributes to blood-brain barrier disruption, microglial activation, and the recruitment of peripheral immune cells.
ATP and UTP: Cytosolic ATP is released into the extracellular space, where it activates P2X7 receptors on microglia, driving NLRP3 inflammasome activation and IL-1β release. ATP also acts as a chemoattractant, recruiting immune cells to the site of neuronal death.
Mitochondrial DNA (mtDNA): mtDNA released from necroptotic neurons activates the NLRP3 inflammasome through the cyclic GMP-AMP synthase (cGAS)-STING pathway. mtDNA also triggers TLR9 on microglia and astrocytes.
S100 proteins: S100A8/A9 (calprotectin) released from necroptotic neurons activate RAGE and TLR4, amplifying neuroinflammation.
The DAMP cascade created by necroptotic neuronal death has several consequences for disease progression. First, it recruits and activates microglia and astrocytes at the site of death, creating a chronic inflammatory focus. Second, it triggers proliferation of microglia (through M-CSF and GM-CSF signaling), expanding the microglial population. Third, the cytokines released by activated glia (TNF-α, IL-1β, IL-6) trigger necroptosis in neighboring neurons, creating a wave of inflammatory neuronal death that spreads through the affected brain region. Fourth, the inflammatory environment promotes further aggregation of pathological proteins (Aβ, tau, αSyn), increasing the load of necroptosis triggers. [5:1]
This feedforward cycle explains why necroptosis is so destructive in neurodegenerative disease: it is not just a form of cell death but an amplifier of the entire pathogenic cascade.
Necrostatin-1: The prototypical necroptosis inhibitor, Nec-1 was identified in a chemical library screen as a small molecule that blocked TNF-α-induced necrotic cell death. [1:1] Nec-1 binds to the hydrophobic pocket of RIPK1, stabilizing an inactive conformation and preventing both its kinase activity and its ability to recruit RIPK3. While useful as a research tool, Nec-1 has limitations: moderate potency (IC50 ~ 100 nM), metabolic instability (short half-life in vivo), and off-target effects at high concentrations.
Necrostatin-1s (7-Cl-O-Nec): An improved analog with better metabolic stability and selectivity. It has been widely used in pre-clinical studies of neurodegeneration and has demonstrated efficacy in AD, PD, stroke, and TBI models.
Compound 8 (C8): A RIPK1 inhibitor with improved pharmacokinetics and blood-brain barrier penetration. It provides neuroprotection in models of stroke and TBI when administered post-injury.
Daprodustat: Originally developed as a HIF prolyl hydroxylase inhibitor for anemia, later found to be a potent RIPK1 inhibitor. It shows neuroprotective effects in multiple neurodegeneration models.
GSK'872: A potent RIPK3 kinase inhibitor that blocks necroptosis in cellular models. However, GSK'872 also inhibits related kinases (RIPK1, IRAK1/2) and its specificity for RIPK3 in vivo is debated. It has been used in pre-clinical studies but is not suitable for clinical development due to off-target effects.
UHCL15-9: A selective MLKL inhibitor that blocks MLKL oligomerization without affecting RIPK1 or RIPK3. This compound directly targets the executioner step of necroptosis and may have fewer off-target effects than kinase inhibitors.
Genetic approaches: shRNA-mediated knockdown of RIPK3 or MLKL, CRISPR-Cas9 gene editing, and dominant-negative mutants (e.g., RIPK3-K376A, MLKL-RP) provide proof-of-concept for necroptosis targeting. In animal models, crossing RIPK3-KO or MLKL-KO mice onto AD or PD mouse models provides robust neuroprotection and cognitive/motor improvement.
Several natural compounds have necroptosis-inhibitory activity. Resveratrol (a polyphenol found in red wine and grapes) inhibits necroptosis through activation of SIRT1 and deacetylation of RIPK1. Curcumin blocks RIPK1 activation through antioxidant mechanisms. Nicotinamide (vitamin B3) and its derivatives (nicotinamide riboside, NMN) reduce necroptotic sensitivity by boosting NAD+ levels and supporting sirtuin activity. These compounds have been explored in neurodegeneration models with mixed results — promising in vitro, variable in vivo due to pharmacokinetic limitations.
Translating necroptosis inhibitors to the clinic requires biomarkers that identify patients with active necroptosis who might benefit from treatment. [17] Candidate biomarkers include:
Plasma/CSF RIPK1 and RIPK3: Elevated levels of these kinases in peripheral blood or cerebrospinal fluid may indicate ongoing necroptosis in the brain. RIPK1 is detectable in plasma and increases in neurodegenerative disease.
p-MLKL in peripheral blood mononuclear cells (PBMCs): Phosphorylated MLKL in circulating immune cells may serve as a proxy for systemic necroptosis activity.
DAMPs in plasma: HMGB1, cell-free mtDNA, and S100A8/A9 are elevated in the plasma of AD and PD patients and may indicate necroptotic activity.
Neuroimaging: PET ligands targeting RIPK1 or activated microglia may enable visualization of necroptosis-related neuroinflammation in living patients.
An optimal clinical trial design for a necroptosis inhibitor in neurodegeneration would be: (1) enroll patients with early-stage AD (MCI) or PD (Hoehn-Yahr 1-2) who have biomarker evidence of active neuroinflammation; (2) treat with an oral RIPK1 inhibitor for 12-24 months; (3) monitor for slowing of cognitive/motor decline, reduction in neuroinflammatory PET signal, and decreased DAMP levels in plasma/CSF; (4) use biomarkers of necroptosis pathway activity (p-MLKL, RIPK1/RIPK3 levels) as pharmacodynamic markers of target engagement.
Given that necroptosis inhibitors are likely to be disease-modifying (slowing progression) rather than symptomatic, the primary endpoint should be a reduction in the rate of decline on cognitive (ADAS-Cog, CDR-SB for AD; MDS-UPDRS for PD) or functional scales.
Several challenges face necroptosis-targeting therapies. First, timing may be critical: necroptosis may be most important early in disease when the triggers (Aβ, tau, αSyn) are building up, and may be less relevant in end-stage disease. Second, the chronic nature of neurodegeneration means that treatment would need to be long-term, raising safety concerns about inhibiting a cell death pathway (even one that is "programmed," complete RIPK1 inhibition could theoretically interfere with essential signaling). Third, the inflammatory component of necroptosis may also have beneficial aspects (immune surveillance, clearance of damaged cells), and long-term inhibition could theoretically impair these functions.
Single-cell transcriptomic and proteomic approaches are revealing which neuronal subtypes are most vulnerable to necroptosis in neurodegeneration. In AD, GABAergic interneurons (particularly parvalbumin and somatostatin subtypes) show heightened necroptosis sensitivity, contributing to circuit disinhibition. In PD, distinct subpopulations of dopaminergic neurons show differential vulnerability — those with low calcium channel expression are more resistant, while those with high L-type calcium channel expression are more vulnerable to necroptosis.
The recognition that necroptosis can proceed through RIPK1-independent pathways (ZBP1, TRIF) suggests that RIPK1 inhibitors may not be sufficient to block all forms of necroptotic death. Developing inhibitors that target the convergence point (RIPK3 or MLKL) may be more effective, though the challenges of targeting these proteins pharmacologically are greater.
The convergence of Aβ, tau, αSyn, mHTT, and SOD1 on necroptosis suggests that this cell death pathway represents a final common pathway for proteotoxicity-induced neuronal death. This has profound therapeutic implications: a single necroptosis inhibitor could potentially slow disease progression across multiple neurodegenerative conditions, provided the inhibitor reaches the CNS and is safe for chronic use.
The most promising therapeutic strategy may be combination therapy: anti-aggregates (anti-Aβ antibodies, anti-tau antibodies, anti-αSyn antibodies or small molecules) to reduce the triggers of necroptosis, plus necroptosis inhibitors to protect neurons from the triggers that remain. This approach addresses both the upstream pathology and the downstream execution of neuronal death, maximizing the potential for disease modification.
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