, Volume 20, Issue 10, pp 1296–1306 | Cite as

Morin mitigates acetaminophen-induced liver injury by potentiating Nrf2 regulated survival mechanism through molecular intervention in PHLPP2-Akt-Gsk3β axis

  • Fatima Rizvi
  • Alpana Mathur
  • Poonam KakkarEmail author
Original Paper


Acetaminophen (APAP) is frequently taken to relieve pain. Staggered APAP overdoses have been reported to cause acetaminophen-induced liver injury (AILI). Identification of efficacious therapeutic modalities to address complications imposed by accidental/intentional long-term APAP ingestion is needed. Morin, a plant-derived phytochemical, possesses a multitude of pharmacological properties including hepatoprotective action; however, the underlying mechanisms have been inadequately explored. Our present report demonstrates significant attenuation of APAP-mediated liver injury by morin supplementation in vivo as indicated by reduction in histological and serum markers of hepatotoxicity. Morin not only limited necroinflammation as revealed by reduced HMGB1 release, NALP3 and caspase-1 maturation, but also suppressed oxidative stress and mitochondrial dysfunction. This suggests that morin may have exerted its cytoprotective role by way of early intervention in the pathway leading to perpetuation of AILI. Morin reinforced cellular defenses by suppressing Nrf2 ubiquitination and promoting nuclear Nrf2 retention as well as ARE-Nrf2 binding affinity. The effects were observed to be a result of molecular intervention in the activity of PHLPP2, a phosphatase previously reported by us to subdue cellular Nrf2 responses via Fyn kinase activation. Morin was observed to inhibit APAP-induced increase in PHLPP2 activity ex vivo as well as its association with cellular target Akt1. As a result, morin prevented oxidative stress induced deactivation of Akt (Ser473) leading to suppression in GSK3β and Fyn kinase activation. The study supports the inhibitory action of morin against PHLPP2-regulated Nrf2-suppression and hence indentifies Nrf2-potentiating property of morin that may be exploited in developing novel therapeutic strategy to address AILI.


PHLPP2 Nrf2 Acetaminophen Fyn kinase Oxidative stress Flavonoid 



Apoptosis inducing factor


Acetaminophen-induced liver injury


Alkaline phosphatase


Alanine aminotransferase




Antioxidant redox element


Aspartate transaminase


Adenosine triphosphate






Damage-associated molecular pattern molecules


2′,7′-Dichlorofluorescein diacetate




Enzyme-linked immunosorbent assay


Endonuclease G


Fluorescein isothiocyanate


Glyceraldehyde phosphate dehydrogenase


Glutathione peroxidase


Glutathione reductase




Glutathione disulfide


Glutathione S-transferase


Hematoxylin and eosin


High-mobility group box 1


Hemeoxygenase 1


5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethylbenzimidazolyl carbocyanine iodide


Kelch-like ECH-associated protein-1


Lactate dehydrogenase


3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide




Nicotinamide adenine dinucleotide


Nicotinamide adenine dinucleotide reduced


NACHT, LRR and PYD domains-containing protein 3




NAD(P)H quinine oxidoreductase 1


Nuclear factor erythroid 2-related factor 2


Non-steroidal anti-inflammatory drugs


PH-domain and Leucine rich repeat protein phosphatase 2


Propidium iodide


Polyvinylidene fluoride


Red blood cell


Reactive oxygen species


Standard error of the mean


Superoxide dismutase


Thioredoxin reductase



We are grateful to the Institutional Manuscript Review Committee of CSIR-IITR for allotting communication number 3253 for the manuscript. Financial support was received from CSIR Network Project-BSC 0111 and BSC 0106. First author acknowledges Council of Scientific and Industrial Research (CSIR), India, for award of fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

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Supplementary material 1 (TIFF 1110 kb)
10495_2015_1160_MOESM2_ESM.tif (318 kb)
Supplementary material 2 (TIFF 318 kb)
10495_2015_1160_MOESM3_ESM.docx (29 kb)
Supplementary material 3 (DOCX 29 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Academy of Scientific and Innovative ResearchLucknowIndia
  2. 2.Herbal Research Section, Food Drug and Chemical Toxicology DivisionCouncil of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR)LucknowIndia

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