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5 new MANF research articles. Dumping here.
1. MANF attenuates cholestatic liver injury by altering GRP78-PERK association
Jinhang Zhang et al. Biochem Pharmacol. 2026.
Cholestatic liver injury (CLI) arises from hepatic bile acid overload due to impaired bile flow, often progressing to liver fibrosis and even failure. While endoplasmic reticulum (ER) stress activation is a key driver for CLI pathogenesis, its regulatory mechanisms remain incompletely understood. In this study, we identify that mesencephalic astrocyte-derived neurotrophic factor (MANF), as an ER-resident protein, was markedly upregulated within the livers of both CLI patients and murine models. In rodents with bile duct ligation (BDL)-triggered cholestasis, hepatic-specific MANF knockout aggravated bile acid overload, liver injury, and inflammation by hyperactivating ER stress. Furthermore, hepatic-specific MANF deletion exacerbated tunicamycin-induced ER stress and hepatocyte damage, whereas hepatic MANF overexpression conferred protection against ER stress and liver injury. Mechanistically, MANF directly interacts with GRP78, altering the association between GRP78 and PERK and thereby inhibiting PERK-eIF2α-ATF4 pathway activation. Disruption of the GRP78-PERK axis abolished MANF-mediated ER stress attenuation. Hepatic MANF overexpression mitigated BDL-induced liver damage via deactivating PERK-ATF4 signaling. Our studies unveil MANF serving as a pivotal regulator of ER stress in CLI, functioning through the GRP78-PERK-ATF4 axis. These results not only provide novel mechanistic insights into cholestatic liver injury but also position MANF as a potential candidate therapeutic target for CLI.
https://pubmed.ncbi.nlm.nih.gov/42700805/
2. MAM-Localized MANF Counteracts Microinflammatory Stress to Attenuate Mitochondrial Dysfunction and Cataractogenesis in High Myopia
Xin Liu et al. Adv Sci (Weinh). 2026.
Chronic microinflammation drives tissue degeneration, particularly in age-related and metabolic diseases, yet how it disrupts inter-organelle communication that leads to cellular failure remains largely unexplored. Utilizing highly myopic cataract (HMC) as a paradigm, we uncover a non-canonical defense mechanism centered on mitochondria-associated endoplasmic reticulum membranes (MAMs). Under microinflammatory stress, mesencephalic astrocyte-derived neurotrophic factor (MANF), conventionally recognized as an ER-resident protein, specifically localizes to MAMs in lens epithelial cells (LECs). At this critical interface, MANF acts as a metabolic sensor that safeguards calcium homeostasis by directly promoting the ubiquitin-mediated degradation of the sarco/endoplasmic reticulum Ca2 +-ATPase 2 (SERCA2). Microinflammation-induced MANF deficiency triggers pathological SERCA2 accumulation, MAM hyperassembly, disrupted ER-to-mitochondria calcium coupling, profound oxidative stress, and mitochondrial bioenergetic collapse, culminating in LEC apoptosis. We validate this pathogenic cascade using human HMC specimens, a unilateral defocus-induced high myopia model, and a novel lens-specific Manf conditional knockdown mouse. Strikingly, in vivo AAV2-mediated MANF gene delivery successfully normalizes MAM architecture, rescues mitochondrial function, and prevents cataractogenesis, demonstrating therapeutic reversibility. In summary, this study establishes the MANF-SERCA2 axis at the MAM interface as a critical pathway linking microinflammation to organelle dysfunction and proposes this interaction as a promising therapeutic target for cataractogenesis and other microinflammation-driven degenerations.
https://pubmed.ncbi.nlm.nih.gov/42419372/
3. MANF in the lateral septum dynamically regulates endoplasmic reticulum function in chronic stress response
Jinmei Ye et al. Transl Psychiatry. 2026.
Major depressive disorder (MDD) is primarily influenced by chronic stress as an environmental risk factor, yet the precise temporal mechanisms governing disease initiation and progression remain largely undefined. This study systematically characterized the dynamic molecular adaptations within the lateral septum (LS), a limbic hub crucial for stress processing, across the critical transition from acute to chronic stress exposure. Through longitudinal transcriptomic analysis, we identified a biphasic dynamic response in the LS, initial widespread gene upregulation during acute stress phases progressively shifted to predominant downregulation as stress persisted. This temporal reprogramming was characterized by persistent activation of the endoplasmic reticulum (ER) stress pathway, particularly involving the unfolded protein response. Most notably, the ER stress-related factor mesencephalic astrocyte-derived neurotrophic factor (MANF) exhibited a striking temporal pattern, showing rapid upregulation during acute stress, followed by sustained suppression throughout the chronic stress phases. Functional investigations established that LS-specific MANF knockdown directly induced ER dysfunction, impaired structural and functional synaptic plasticity, and promoted depressive-like behaviors. Conversely, MANF overexpression effectively rescued these pathological phenotypes. Our findings illuminate the crucial temporal dimension of LS transcriptomic reorganization in MDD pathogenesis and identify MANF as a pivotal regulator bridging ER stress adaptation to neural circuit dysfunction, providing a mechanistic foundation for early intervention strategies and biomarker development.
https://pubmed.ncbi.nlm.nih.gov/42425961/
4. MANF safeguards mitochondria-associated endoplasmic reticulum membrane integrity in nucleus pulposus-derived mesenchymal stem cells to maintain homeostasis of the intervertebral disc
Chenhao Zhao et al. Cell Biol Toxicol. 2026.
Background: Intervertebral disc (IVD) degeneration (IDD) is a leading cause of low back pain, with limited treatment options. The degenerative disc's harsh microenvironment promotes nucleus pulposus-derived mesenchymal stem cells (NP-MSCs) death and hinders self repair. Mesencephalic astrocyte-derived neurotrophic factor (MANF), an atypical neurotrophic factor, has protective effects in degenerative diseases. However, its role in IDD is unclear.
Methods: Assessment of MANF expression was conducted in both human nucleus pulposus tissues and a rat IVD puncture model. An in vitro model of degeneration was established by acid treatment of NP-MSCs, and the functional role of MANF was explored through its knockdown and overexpression. RNA sequencing was employed to identify downstream targets. The therapeutic potential of MANF-overexpressing NP-MSCs was evaluated in a rat puncture model.
Results: MANF expression was markedly downregulated in degenerated IVD tissues from both human patients and rat models. Correspondingly, in vitro experiments demonstrated that MANF knockdown exacerbated, while its overexpression mitigated, acid-induced apoptosis of NP-MSCs. Mechanistically, MANF attenuated mitochondrial dysfunction and ER stress of NP-MSCs under acidic conditions by maintaining MAM integrity, as demonstrated by the complete abolition of this protection upon treatment with the MAM uncoupler FATE1. Transcriptomic analysis and subsequent validation identified receptor expression-enhancing protein 1 (REEP1) as a critical downstream effector through which MANF safeguards MAM integrity. We further elucidated that MANF upregulates REEP1 expression by directly inhibiting miR-33b-5p. In vivo, transplantation of MANF-overexpressing NP-MSCs effectively attenuated IDD in a rat model.
Conclusion: MANF protected NP-MSCs from acidosis by sustaining MAM integrity via the MiR-33b-5p/REEP1 axis. These findings reveal MANF's mechanism and therapeutic potential for IDD.
https://pubmed.ncbi.nlm.nih.gov/42426407/
5. MANF clears mutant uromodulin in human kidney organoids of autosomal dominant tubulointerstitial kidney disease
Autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD) is one of the leading hereditary kidney diseases. Currently there is no targeted treatment. To illuminate human relevance of mesencephalic astrocyte-derived neurotrophic factor (MANF)-based therapy, we have established patient induced pluripotent stem cell (iPSC)-derived kidney organoid model carrying UMOD p.H177-R185del, the leading mutation causing ADTKD. We have discovered that MANF can directly bind and repress ER calcium release channel IP3R1, thus enhancing AMPK-induced autophagy in a TRIB3-dependent manner. The therapeutic implication of this finding may well be extended to other protein misfolding diseases.
https://www.jci.org/articles/view/205631
1. MANF attenuates cholestatic liver injury by altering GRP78-PERK association
Jinhang Zhang et al. Biochem Pharmacol. 2026.
Cholestatic liver injury (CLI) arises from hepatic bile acid overload due to impaired bile flow, often progressing to liver fibrosis and even failure. While endoplasmic reticulum (ER) stress activation is a key driver for CLI pathogenesis, its regulatory mechanisms remain incompletely understood. In this study, we identify that mesencephalic astrocyte-derived neurotrophic factor (MANF), as an ER-resident protein, was markedly upregulated within the livers of both CLI patients and murine models. In rodents with bile duct ligation (BDL)-triggered cholestasis, hepatic-specific MANF knockout aggravated bile acid overload, liver injury, and inflammation by hyperactivating ER stress. Furthermore, hepatic-specific MANF deletion exacerbated tunicamycin-induced ER stress and hepatocyte damage, whereas hepatic MANF overexpression conferred protection against ER stress and liver injury. Mechanistically, MANF directly interacts with GRP78, altering the association between GRP78 and PERK and thereby inhibiting PERK-eIF2α-ATF4 pathway activation. Disruption of the GRP78-PERK axis abolished MANF-mediated ER stress attenuation. Hepatic MANF overexpression mitigated BDL-induced liver damage via deactivating PERK-ATF4 signaling. Our studies unveil MANF serving as a pivotal regulator of ER stress in CLI, functioning through the GRP78-PERK-ATF4 axis. These results not only provide novel mechanistic insights into cholestatic liver injury but also position MANF as a potential candidate therapeutic target for CLI.
https://pubmed.ncbi.nlm.nih.gov/42700805/
2. MAM-Localized MANF Counteracts Microinflammatory Stress to Attenuate Mitochondrial Dysfunction and Cataractogenesis in High Myopia
Xin Liu et al. Adv Sci (Weinh). 2026.
Chronic microinflammation drives tissue degeneration, particularly in age-related and metabolic diseases, yet how it disrupts inter-organelle communication that leads to cellular failure remains largely unexplored. Utilizing highly myopic cataract (HMC) as a paradigm, we uncover a non-canonical defense mechanism centered on mitochondria-associated endoplasmic reticulum membranes (MAMs). Under microinflammatory stress, mesencephalic astrocyte-derived neurotrophic factor (MANF), conventionally recognized as an ER-resident protein, specifically localizes to MAMs in lens epithelial cells (LECs). At this critical interface, MANF acts as a metabolic sensor that safeguards calcium homeostasis by directly promoting the ubiquitin-mediated degradation of the sarco/endoplasmic reticulum Ca2 +-ATPase 2 (SERCA2). Microinflammation-induced MANF deficiency triggers pathological SERCA2 accumulation, MAM hyperassembly, disrupted ER-to-mitochondria calcium coupling, profound oxidative stress, and mitochondrial bioenergetic collapse, culminating in LEC apoptosis. We validate this pathogenic cascade using human HMC specimens, a unilateral defocus-induced high myopia model, and a novel lens-specific Manf conditional knockdown mouse. Strikingly, in vivo AAV2-mediated MANF gene delivery successfully normalizes MAM architecture, rescues mitochondrial function, and prevents cataractogenesis, demonstrating therapeutic reversibility. In summary, this study establishes the MANF-SERCA2 axis at the MAM interface as a critical pathway linking microinflammation to organelle dysfunction and proposes this interaction as a promising therapeutic target for cataractogenesis and other microinflammation-driven degenerations.
https://pubmed.ncbi.nlm.nih.gov/42419372/
3. MANF in the lateral septum dynamically regulates endoplasmic reticulum function in chronic stress response
Jinmei Ye et al. Transl Psychiatry. 2026.
Major depressive disorder (MDD) is primarily influenced by chronic stress as an environmental risk factor, yet the precise temporal mechanisms governing disease initiation and progression remain largely undefined. This study systematically characterized the dynamic molecular adaptations within the lateral septum (LS), a limbic hub crucial for stress processing, across the critical transition from acute to chronic stress exposure. Through longitudinal transcriptomic analysis, we identified a biphasic dynamic response in the LS, initial widespread gene upregulation during acute stress phases progressively shifted to predominant downregulation as stress persisted. This temporal reprogramming was characterized by persistent activation of the endoplasmic reticulum (ER) stress pathway, particularly involving the unfolded protein response. Most notably, the ER stress-related factor mesencephalic astrocyte-derived neurotrophic factor (MANF) exhibited a striking temporal pattern, showing rapid upregulation during acute stress, followed by sustained suppression throughout the chronic stress phases. Functional investigations established that LS-specific MANF knockdown directly induced ER dysfunction, impaired structural and functional synaptic plasticity, and promoted depressive-like behaviors. Conversely, MANF overexpression effectively rescued these pathological phenotypes. Our findings illuminate the crucial temporal dimension of LS transcriptomic reorganization in MDD pathogenesis and identify MANF as a pivotal regulator bridging ER stress adaptation to neural circuit dysfunction, providing a mechanistic foundation for early intervention strategies and biomarker development.
https://pubmed.ncbi.nlm.nih.gov/42425961/
4. MANF safeguards mitochondria-associated endoplasmic reticulum membrane integrity in nucleus pulposus-derived mesenchymal stem cells to maintain homeostasis of the intervertebral disc
Chenhao Zhao et al. Cell Biol Toxicol. 2026.
Background: Intervertebral disc (IVD) degeneration (IDD) is a leading cause of low back pain, with limited treatment options. The degenerative disc's harsh microenvironment promotes nucleus pulposus-derived mesenchymal stem cells (NP-MSCs) death and hinders self repair. Mesencephalic astrocyte-derived neurotrophic factor (MANF), an atypical neurotrophic factor, has protective effects in degenerative diseases. However, its role in IDD is unclear.
Methods: Assessment of MANF expression was conducted in both human nucleus pulposus tissues and a rat IVD puncture model. An in vitro model of degeneration was established by acid treatment of NP-MSCs, and the functional role of MANF was explored through its knockdown and overexpression. RNA sequencing was employed to identify downstream targets. The therapeutic potential of MANF-overexpressing NP-MSCs was evaluated in a rat puncture model.
Results: MANF expression was markedly downregulated in degenerated IVD tissues from both human patients and rat models. Correspondingly, in vitro experiments demonstrated that MANF knockdown exacerbated, while its overexpression mitigated, acid-induced apoptosis of NP-MSCs. Mechanistically, MANF attenuated mitochondrial dysfunction and ER stress of NP-MSCs under acidic conditions by maintaining MAM integrity, as demonstrated by the complete abolition of this protection upon treatment with the MAM uncoupler FATE1. Transcriptomic analysis and subsequent validation identified receptor expression-enhancing protein 1 (REEP1) as a critical downstream effector through which MANF safeguards MAM integrity. We further elucidated that MANF upregulates REEP1 expression by directly inhibiting miR-33b-5p. In vivo, transplantation of MANF-overexpressing NP-MSCs effectively attenuated IDD in a rat model.
Conclusion: MANF protected NP-MSCs from acidosis by sustaining MAM integrity via the MiR-33b-5p/REEP1 axis. These findings reveal MANF's mechanism and therapeutic potential for IDD.
https://pubmed.ncbi.nlm.nih.gov/42426407/
5. MANF clears mutant uromodulin in human kidney organoids of autosomal dominant tubulointerstitial kidney disease
Autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD) is one of the leading hereditary kidney diseases. Currently there is no targeted treatment. To illuminate human relevance of mesencephalic astrocyte-derived neurotrophic factor (MANF)-based therapy, we have established patient induced pluripotent stem cell (iPSC)-derived kidney organoid model carrying UMOD p.H177-R185del, the leading mutation causing ADTKD. We have discovered that MANF can directly bind and repress ER calcium release channel IP3R1, thus enhancing AMPK-induced autophagy in a TRIB3-dependent manner. The therapeutic implication of this finding may well be extended to other protein misfolding diseases.
https://www.jci.org/articles/view/205631
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