**1. Introduction**

The thymus is the primary lymphoid organ composed of multiple cell types creating a unique microenvironment for producing immunocompetent T cells from bone marrowderived T cell progenitors/precursors, thereby playing a crucial role in the development of the host adaptive immune system. T cells are not only trained to recognize and eliminate foreign antigens during development in the thymus, but also to tolerate self-antigens through positive and negative selection. This thymic education of T cells is mainly orchestrated by thymic epithelial cells (TECs) that play a pivotal role in the multistep processes, including the homing and clonal expansion, survival, and maturation of the immature T cells [1].

**Citation:** Song, W.H.; Kim, H.-Y.; Lim, Y.S.; Hwang, S.Y.; Lee, C.; Lee, D.Y.; Moon, Y.; Song, Y.J.; Yoon, S. Fish Collagen Peptides Protect against Cisplatin-Induced Cytotoxicity and Oxidative Injury by Inhibiting MAPK Signaling Pathways in Mouse Thymic Epithelial Cells. *Mar. Drugs* **2022**, *20*, 232. https:// doi.org/10.3390/md20040232

Academic Editor: Bill J. Baker

Received: 18 February 2022 Accepted: 24 March 2022 Published: 28 March 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

The thymus is a peculiar organ in our body that undergoes progressive involution or atrophy with age. It is called age-related or physiological thymic involution (or atrophy), resulting in a deterioration of its T cell generation ability. In addition, many stimuli including infection, radiation, stress, toxic substances, pregnancy, steroid hormones, malnutrition, immunosuppressive drugs, such as cyclosporine and dexamethasone, chemotherapeutic agents, such as cyclophosphamide, cisplatin, methotrexate, and taxanes, dangerous substances, and harmful biological processes can cause a condition known as acute or accidental thymic involution (or atrophy) [2,3]. Regardless of the type and causative agents of thymic involution, it is usually connected with primary TEC injury [4–6], ultimately leading to a decreased thymus production and outward migration of mature T cells, and increased severity and susceptibility to infections, cancer, and autoimmune diseases [7–9].

Oxidative stress is a disturbance in the balance between reactive oxygen species (ROS) activities and antioxidant defense mechanisms associated with detoxification of the harmful effects of ROS, which affects the induction of thymic involution [10]. Many endogenous and exogenous stimuli trigger ROS production, damaging DNA, cellular proteins/lipids, and cell membrane, and inducing an inflammatory response, leading to apoptotic or necrotic cell death [11].

Chemotherapies with platinum-based anticancer drugs are standard treatments for various cancers, including ovarian cancer, cervical cancer, lung cancer, head and neck cancer, bladder cancer, and lymphoma [12,13]. Cisplatin was the first widely used platinum-based chemotherapy drug and has been the basis agen<sup>t</sup> for treating a broad spectrum of cancers [14]. However, despite its huge potential as a chemotherapy regimen, cisplatin has been linked to several toxic side effects, including nephrotoxicity, lymphosuppression, myelosuppression, ototoxicity, cardiotoxicity, hepatotoxicity, and neurotoxicity, through various mechanisms, such as oxidative stress, apoptosis, inflammation, and autophagy [15,16]. Cisplatin mainly displays its cytotoxic activity by tipping the redox scale favoring oxidative stress, leading to mitochondrial membrane permeabilization and DNA damage [17,18].

Currently, fish collagen peptides (FCP) are gaining increasing attention due to their purported safety [19–21] and diverse biological activities, such as antioxidant activity [22,23], neuroprotective effects [24], anti-aging effects [25], and wound healing effects [26]. Furthermore, oral administration of FCP was reported to diminish the production of proinflammatory cytokines, such as tumor necrosis factorα (TNFα) and nitric oxide (NO) in rat synoviocytes, and NO and C-reactive protein in diabetic patients with chronic inflammation [27,28]. However, there are still many questions left unanswered about the efficacy of FCP in protecting TEC injury.

Here, the present study shows that FCP protects TECs against cisplatin-induced cytotoxic and oxidative injury by inhibiting MAPK signal transduction pathways.
