Education:
- PhD University of Kerala, India
- Post Doctoral Fellowships-Kobe Pharmaceutical University (Japan) and University of Cambridge (UK)
Clinical/Research Interests:
The primary goal of research in Sathyaseelan lab is to understand how aging drives chronic inflammation and diseases, with a particular focus on chronic liver diseases (CLD) such as metabolic dysfunction-associated fatty liver disease (MAFLD) and hepatocellular carcinoma (HCC). Our lab focuses on investigating how necroptosis, an inflammatory form of cell death, contributes to chronic inflammation and liver diseases in aging and obesity. Additionally, we explore how the non-necroptotic functions of MLKL, the key effector of the necroptosis pathway, influence these processes. Our laboratory critically contributed to understanding of the role of necroptosis in aging and our ongoing studies aim to uncover mechanisms by which necroptosis pathway or MLKL drives chronic inflammation and contributes to the progression of CLD. Our goal is to discover novel therapeutic strategies targeting necroptosis or MLKL to improve health outcomes in aging and metabolic disorders.
Necroptosis and Inflammation in Aging. Aging is associated with chronic, low-grade inflammation, known as "inflammaging," which is linked to numerous age-related diseases. While necroptosis is known to drive chronic inflammation, its role in aging and inflammaging remains unclear. Our research has shown that necroptosis markers increase with age in various tissues in mice, and inhibiting this pathway can reduce inflammation (proinflammatory cytokines and proinflammatory macrophages), cellular senescence (a key contributor to age-related inflammation), and CLD. Our ongoing research investigates how necroptosis in various liver cells (hepatocytes and macrophages) promotes liver inflammation, senescence, and the progression of MASLD and HCC. Our goal is to identify therapeutic strategies that can reduce inflammation and cellular senescence, and slow the progression of age-related diseases, promoting healthier aging.
Liver-Brain Axis and Cognitive decline in Aging. A growing body of evidence links liver inflammation and chronic liver diseases, such as MASLD and HCC, to neuroinflammation and cognitive decline in humans. While patients with these conditions often exhibit early signs of cognitive dysfunction, the mechanisms driving these effects, particularly the role of the liver-brain axis, are not fully understood. Our research focuses on the impact of liver inflammation and disease on cognitive function, specifically examining how liver dysfunction contributes to neuroinflammation and cognitive impairment in aging. By exploring the molecular mechanisms that link liver diseases to neuroinflammation, we aim to uncover potential therapeutic targets that can reduce systemic inflammation, enhance brain health, and mitigate cognitive decline in aging populations.
Obesity-Driven HCC and the Role of MLKL. Obesity is a major risk factor for HCC, one of the leading causes of cancer-related deaths worldwide. Yet, mechanisms driving HCC in obesity is poorly understood. Chronic inflammation is one of the proposed mediators of obesity-driven HCC. Our studies have shown that genetic deletion of MLKL reduces HCC in mouse models of MASLD. Our ongoing research explores liver cell type specific effects of necroptotic and non-necroptotic roles of MLKL on tumor development and progression in obesity. Our goal is to identify therapeutic targets that could reduce the risk of HCC in obese individuals and improve patient outcomes.
MLKL in Adipose Tissue Metabolism and Energy Expenditure. Obesity and metabolic dysfunction are linked to impaired adipose tissue metabolism and reduced energy expenditure. Our research has revealed that MLKL inhibition promotes anti-obesity effects by enhancing adipose tissue metabolism, increasing energy expenditure, and improving insulin sensitivity, indicating that MLKL plays a role beyond cell death. We aim to further understand how MLKL regulates adipose tissue metabolism and energy balance in the context of obesity, with the long-term goal of developing new therapies to combat obesity and improve metabolic health.
Select Publications:
1. 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.
2. Deepa SS, Thadathil N, Corral J, Mohammed S, Pham S, Rose H, Kinter MT, Richardson A, Díaz-García CM. MLKL overexpression leads to Ca2+ and metabolic dyshomeostasis in a neuronal cell model. Cell Calcium. 2024 May;119:102854. PMID: 38430790; PMCID: PMC10990772.
3. 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.
4. Thadathil N, Selvarani R, Mohammed S, Nicklas EH, Tran AL, Kamal M, Luo W, Brown JL, Lawrence MM, Borowik AK, Miller BF, Van Remmen H, Richardson A, Deepa SS. Senolytic treatment reduces cell senescence and necroptosis in Sod1 knockout mice that is associated with reduced inflammation and hepatocellular carcinoma. Aging Cell. 2022 Aug;21(8):e13676. PMID: 35869934; PMCID: PMC9381894.
5. 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.
Link to full publication list >