Education:
- Ph.D. Biochemistry, University of Kerala, India
- Postdoctoral fellowship: Kobe Pharmaceutical University, Japan
- Postdoctoral fellowship: University of Cambridge, UK
Clinical/Research Interests:
Chronic liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC), are growing global health challenges driven by aging and obesity. These conditions not only affect the liver but also contribute to systemic issues such as insulin resistance, cardiovascular disease, and cognitive decline. Despite their prevalence, effective therapies targeting their root causes remain limited.
Our lab investigates how aging and obesity reprogram cellular pathways, particularly inflammation, cell death, and mitochondrial dysfunction, to drive the onset and progression of chronic liver disease. A central focus of our work is Mixed Lineage Kinase Domain-Like protein (MLKL), a critical effector of necroptosis that also plays non-canonical roles in extracellular vesicle (EV) release, mitochondrial regulation, and lipid metabolism. By uncovering the molecular links between aging, obesity, and liver disease, we aim to identify early biomarkers, discover novel therapeutic targets, and improve both liver and systemic health.
Key Research Areas
Liver-Brain Axis and Cognitive Decline. We study how liver inflammation in MASLD and HCC contributes to neuroinflammation and cognitive dysfunction. Our work explores liver-to-brain communication via cytokines and EVs, with the goal of identifying targets to protect brain health in aging and liver disease.
Necroptosis and Inflammaging. Chronic, low-grade inflammation, known as inflammaging, is a hallmark of aging. We have shown that inhibiting necroptosis reduces liver inflammation, senescence, and fibrosis in aged mice. Current efforts focus on cell-type specific roles of necroptosis in hepatocytes and macrophages on inflammaging.
MLKL Beyond Cell Death. Our recent findings show that MLKL, independent of necroptosis, disrupts mitochondrial dynamics, increases oxidative stress, and promotes hepatocyte senescence. We are now dissecting the mechanisms by which MLKL impairs mitochondrial homeostasis, including its impact on fission/fusion proteins and redox pathways.
MLKL in Obesity-Driven HCC. Obesity significantly increases the risk of HCC. We have demonstrated that hepatocyte-specific deletion of MLKL reduces tumor burden in obese mice. Ongoing studies explore how MLKL contributes to HCC through chronic inflammation, mitochondrial dysfunction, and non-necroptotic signaling.
Funding:
- NIH R01 AG059718: The role of hepatocyte necroptosis and inflammation in liver-brain crosstalk in aging . Sathyaseelan (PI)
- Harold Hamm Diabetes Center-Stepheson Cancer Center Team Science Grant: The Role of Hepatocyte MLKL in Type 2 Diabetes Mellitus-Associated Hepatocellular Carcinoma. Sathyaseelan (PI)
- Oklahoma Center for Adult Stem Cell Research Grant: The role of hepatocyte MLKL on cancer stemlike cells in hepatocellular carcinoma. Sathyaseelan (PI)
Select Publications:
- Mohammed S, Ohene-Marfo P, Jiang C, Peng Z, Thadathil N, Tran A, Nicklas E, Bhaskaran S, Wang D, Selvarani R, Singh A, Yang Z, Ahsan N, Deepa SS. Impact of Mlkl or Ripk3 deletion on age-associated liver inflammation, metabolic health, and lifespan. Geroscience. 2025 Jun;47(3):4465-4483. PMID: 39930289; PMCID: PMC12181141.
- Ohene-Marfo P, Nguyen HVM, Mohammed S, Thadathil N, Tran A, Nicklas EH, Wang D, Selvarani R, Farriester JW, Varshney R, Kinter M, Richardson A, Rudolph MC, Deepa SS. Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High-Fat, High-Fructose, High-Cholesterol Diet Mouse Model. Int J Mol Sci. 2024 Feb 28;25(5):2813. PMID: 38474061; PMCID: PMC10931720.
- Mohammed S, Thadathil N, Ohene-Marfo P, Tran AL, Van Der Veldt M, Georgescu C, Oh S, Nicklas EH, Wang D, Haritha NH, Luo W, Janknecht R, Miller BF, Wren JD, Freeman WM, Deepa SS. Absence of Either Ripk3 or Mlkl Reduces Incidence of Hepatocellular Carcinoma Independent of Liver Fibrosis. Mol Cancer Res. 2023 Sep 1;21(9):933-946. PMID: 37204757; PMCID: PMC10472095.
- Mohammed S, Thadathil N, Selvarani R, Nicklas EH, Wang D, Miller BF, Richardson A, Deepa SS. Necroptosis contributes to chronic inflammation and fibrosis in aging liver. Aging Cell. 2021 Dec;20(12):e13512. PMID: 34761505; PMCID: PMC8672775.
- Mohammed S, Nicklas EH, Thadathil N, Selvarani R, Royce GH, Kinter M, Richardson A, Deepa SS. Role of necroptosis in chronic hepatic inflammation and fibrosis in a mouse model of increased oxidative stress. Free Radic Biol Med. 2021 Feb 20;164:315-328. PMID: 33429022; PMCID: PMC8845573.
Link to full publication list: https://www.ncbi.nlm.nih.gov/myncbi/1dmKRSPGLkpkD/bibliography/public/