My research focuses on two complementary areas: therapeutic drug development and mechanistic studies of aging-related pathways.

The primary goal is to develop novel drug interventions targeting cellular senescence and aging by integrating medicinal chemistry, drug discovery, and aging biology. Using a multidisciplinary approach, including cell-based high-content drug screening, drug design, and machine learning, we have successfully developed several new classes of senotherapeutics with the potential to reduce senescent cell burden, extend healthspan, and treat multiple age-related conditions. We also explore the mechanisms of action of these compounds using multi-omics and chemical biology techniques in cell and animal models to identify novel biomarkers and therapeutic targets.

In parallel, I am also interested in studying the molecular mechanisms of aging-related pathways, with a focus on NF-κB, SIRT6, and SMAD3 signaling. By employing genetic and pharmacological approaches, we aim to elucidate the roles of these key pathways in aging and age-related diseases to provide new insights for therapeutic development.

Zhang, L. J.; Salekeen, R.; Soto-Palma, C.; He, Y.; Elsallabi, O.; Hughes, B.; Nunes, A.; Xu, W.; Zhang, B.; Mohamed, A.; Mcgowan, S.; Angelini, L.; O'Kelly, R.; Kamenecka, T. M.; Niedernhofer, L. J.; Robbins, P. D., Development of novel flavonoid senolytics through phenotypic drug screening and drug design. bioRxiv 2024, 2024.10.27.620529

Zhang, L. J.; Salekeen, R.; Soto-Palma, C.; Elsallabi, O.; Ye, H.; Hughes, B.; Zhang, B.; Nunes, A.; Lee, K.; Xu, W.; Mohamed, A.; Piepgras, E.; McGowan, S. J.; Angelini, L.; O’Kelly, R.; Han, X.; Niedernhofer, L. J.; Robbins, P. D., Identification of lipid senolytics targeting senescent cells through ferroptosis induction. bioRxiv 2024, 2024.10.14.618023

Zhang, L.; Pitcher, L. E.; Prahalad, V.; Niedernhofer, L. J.; Robbins, P. D., Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. FEBS J 2023, 290 (5), 1362-1383

Zhang, L.; Pitcher, L. E.; Yousefzadeh, M. J.; Niedernhofer, L. J.; Robbins, P. D.; Zhu, Y., Cellular senescence: a key therapeutic target in aging and diseases. J Clin Invest 2022, 132 (15), e158450

Zhang, L.; Pitcher, L. E.; Prahalad, V.; Niedernhofer, L. J.; Robbins, P. D., Recent advances in the discovery of senolytics. Mech Ageing Dev 2021, 200, 111587

Zhang, L.; Zhao, J.; Mu, X.; McGowan, S. J.; Angelini, L.; O'Kelly, R. D.; Yousefzadeh, M. J.; Sakamoto, A.; Aversa, Z.; LeBrasseur, N. K.; Suh, Y.; Huard, J.; Kamenecka, T. M.; Niedernhofer, L. J.; Robbins, P. D., Novel small molecule inhibition of IKK/NF-kappaB activation reduces markers of senescence and improves healthspan in mouse models of aging. Aging Cell 2021, 20 (12), e13486

Zhao, J.; Zhang, L.; Lu, A.; Han, Y.; Colangelo, D.; Bukata, C.; Scibetta, A.; Yousefzadeh, M. J.; Li, X.; Gurkar, A. U.; McGowan, S. J.; Angelini, L.; O'Kelly, R.; Li, H.; Corbo, L.; Sano, T.; Nick, H.; Pola, E.; Pilla, S. P. S.; Ladiges, W. C.; Vo, N.; Huard, J.; Niedernhofer, L. J.; Robbins, P. D., ATM is a key driver of NF-kappaB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging. Aging 2020, 12 (6), 4688-4710