Russian Journal of ImmunologyRussian Journal of ImmunologyРоссийский иммунологический журнал1028-72212782-7291Russian Society of Immunology1727810.46235/1028-7221-17278-PEIREVIEWSОБЗОРЫReview ArticlePhysical exercise is the best therapy in reducing interleukin-6 levels as an inflammatory mediator: a systematic reviewФизическая нагрузка: лучшая терапия для снижения уровней воспалительного медиатора ИЛ-6: систематический обзорhttps://orcid.org/0000-0002-5196-6636AyubiNovadriАюбиНовадри
Indonesia

S.Or., M.Kes., Dr.

бакалавр физической культуры, магистр здравоохранения, д-р

novadriayubi@unesa.ac.idhttps://orcid.org/0000-0002-4667-5981WibawaJunian CahyantoВибаваДжуниан Кахианто
Indonesia

S.Or., M.Kes., Master

бакалавр физической культуры, магистр здравоохранения, магистр

juniancahyanto96@stkippgritrenggalek.ac.idhttps://orcid.org/0000-0002-2553-467XLoboJosephЛобоДжозеф
Philippines

Ph.D

кандидат наук

joseph.lobo@bulsu.edu.phhttps://orcid.org/0000-0002-2955-0175KomainiAntonКомаиниАнтон
Indonesia

S.Si., M.Pd., Professor

бакалавр естественных наук, магистр педагогических наук, профессор

antonkomaini@fik.unp.ac.idhttps://orcid.org/0000-0002-9137-5515CallixteCyuzuzoКаллистеКуизузо
Rwanda

M.Sc.

магистр наук

c.cyuzuzo@ur.ac.rwhttps://orcid.org/0000-0003-0249-4908RizkiAinun ZulfikarРизкиАйнум Зульфикар
Indonesia

S.Pd., M.Pd.

бакалавр педагогических наук, магистр педагогических наук

ainun.20015@mhs.unesa.ac.idhttps://orcid.org/0009-0009-7161-385259538274900AfandiAlvinАфандиАлвин
Indonesia

S.Pd., M.Pd.

бакалавр педагогических наук, магистр педагогических наук

alvinafandi09@gmail.comhttps://orcid.org/0000-0001-6081-8590SabillahMuhamad IchsanСабиллаМухамад Иксан
Indonesia

S.Or., M.Or., Dr.

бакалавр в области спортивных (физкультурных) наук, магистр в области спортивных (физкультурных) наук, д-р

muhamadsabillah@unesa.ac.idUniversitas Negeri Surabaya, Surabaya, IndonesiaУниверситет Негери, Сурабая, ИндонезияSTKIP PGRI Trenggalek, Trenggalek, IndonesiaСТКИП ПГРИ, Тренггалек, ИндонезияBulacan State University, Malolos, PhilippinesУниверситет Булакан, Малолос, ФилиппиныUniversitas Negeri Padang, Padang, IndonesiaУниверситит Негери, Паданг, ИндонезияUniversity of Rwanda, Butare, RwandaУниверситет Руанды, Бутаре, Руанда290720251801202629155662105202525072025Copyright ©; 2026, Ayubi N., Wibawa J., Lobo J., Komaini A., Callixte C., Rizki A., Afandi A., Sabillah M.Copyright ©; 2026, Аюби Н., Вибава Д., Лобо Д., Комаини А., Каллисте К., Ризки А., Афанди А., Сабилла М.2026Ayubi N., Wibawa J., Lobo J., Komaini A., Callixte C., Rizki A., Afandi A., Sabillah M.Аюби Н., Вибава Д., Лобо Д., Комаини А., Каллисте К., Ризки А., Афанди А., Сабилла М.https://creativecommons.org/licenses/by/4.0https://rusimmun.ru/jour/article/view/17278

Unhealthy lifestyles such as consuming less nutritious foods, lack of physical activity trigger accelerated aging. Aging occurs due to the accumulation of inflammation in the body such as increased levels of interleukin-6. Interleukin-6 (IL-6) is a major pro-inflammatory cytokine involved in the pathogenesis of various chronic diseases, including cardiovascular disorders, diabetes, and autoimmune conditions. Increased levels of IL-6 are associated with systemic inflammation and poor health outcomes. In recent decades, physical exercise has received attention not only for its role in improving fitness but also as a non-pharmacological intervention to modulate the immune response. Currently, it is not well known how exercise affects the IL-6 response. The underlying mechanisms are also still not clearly understood. The physiological response of exercise to IL-6 is important to know and the underlying molecular mechanisms must be clearly understood in order to understand the stages that occur related to the effect of exercise on increasing IL-6. The purpose of this study was to determine the mechanism by which physical activity lowers interleukin-6 levels.

Materials and methods: In this systematic review study, we searched through literature databases including Science Direct, Web of Science, MEDLINE-Pubmed, and Scopus. Papers published over the past five years that addressed interleukin-6 and physical exercise met as inclusion criteria. The Web of Science, Pubmed, and Science Direct databases were used to locate 126 published papers in total. For this systematic review, ten papers that met the inclusion criteria were selected and examined. Standard operating procedures were evaluated in this study using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: Based on the results of this systematic study, it is evident that chronic exercise reduces IL-6 levels. Immediately after acute physical exercise, IL-6 levels increased. However, there was a downward trend in IL-6 levels during chronic physical exercise. Conclusions: Chronic and regular exercise has been shown to reduce IL-6 levels. as a marker of inflammation. If IL-6 can be suppressed by means of exercise, the inflammation will be reduced, thus inhibiting aging which is triggered by accumulation of inflammatory factors.

Нездоровый образ жизни, в том числе - потребление менее питательных продуктов и недостаток физической активности, ускоряет процесс старения. Старение происходит из-за накопления воспалительных процессов в организме, в частности - повышения уровня интерлейкина-6. Интерлейкин-6 (ИЛ-6) — это основной провоспалительный цитокин, участвующий в патогенезе различных хронических болезней, включая сердечно-сосудистые заболевания, диабет и аутоиммунные состояния. Повышенный уровень ИЛ-6 связан с системным воспалением и ухудшением состояния здоровья. В последние десятилетия физические упражнения привлекают внимание не только своей ролью в улучшении физической формы, но также, как немедикаментозное воздействие с целью модуляции иммунного ответа. В настоящее время мало изучено действие физических упражнений на продукцию ИЛ-6, как и основные механизмы его действия. Важно понимать действие физических упражнений на выработку ИЛ-6, и лежащие в его основе молекулярные механизмы, чтобы разобраться в этапах, связанных с влиянием физических упражнений на повышение уровня ИЛ-6. Цель данного исследования заключалась в определении механизма, посредством которого физическая активность снижает уровень интерлейкина-6. Материалы и методы: В данном систематическом обзоре мы провели поиск в базах данных литературы, включая Science Direct, Web of Science, MEDLINE-Pubmed и Scopus. В анализ включали научные статьи за последние пять лет, посвященные интерлейкину-6 и физическим упражнениям. Для поиска в общей сложности были использованы 126 публикаций из баз данных Web of Science, Pubmed и Science Direct. Для данного систематического обзора было отобрано и изучено десять статей, соответствующих критериям включения. Стандартные рабочие процедуры оценивались с использованием PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Результаты: На основании результатов данного систематического исследования очевидно, что длительные физические упражнения снижают уровень ИЛ-6. Сразу после острых физических нагрузок уровень ИЛ-6 повышался. Однако во время длительных физических упражнений наблюдалась тенденция к снижению уровня ИЛ-6. Выводы. Было показано, что хронические и регулярные физические упражнения снижают уровень ИЛ-6 в качестве маркера воспаления. Если уровень ИЛ-6 можно подавить с помощью физических упражнений, воспаление уменьшится, тем самым замедляя старение, которое наступает при накоплении факторов воспаления.

IL-6physical exerciseinflammationaginglifestylesIL-6физические упражнениявоспалениестарениеобраз жизниAmin M.N., El-Mowafy M., Mobark A., Abass N., Elgaml A. Exercise-induced downregulation of serum interleukin-6 and tumor necrosis factor-alpha in Egyptian handball players. Saudi J. Biol. Sci., 2021, Vol. 28, no. 1, pp. 724-730.Avdhoot P. Lifestyle disorders: an emerging health problem (causes and prevention from nutritional perspective). Res. J. Fam. Commun. Consum. Sci., 2023, Vol. 11, no. 2, pp. 11-14.Barbé-Tuana F., Funchal G., Schmitz C.R.R., Maurmann R.M., Bauer M.E. The interplay between immunosenescence and age-related diseases. Semin. Immunopathol., 2020, Vol. 42, no. 5, pp. 545-557.Barnes P.J. Oxidative stress-based therapeutics in COPD. Redox Biol., 2020, Vol. 33, no. 4, 101544. doi: 10.1016/j.redox.2020.101544.Borsa M., Barandun N., Gräbnitz F., Barnstorf I., Baumann N.S., Pallmer K., Baumann S., Stark D., Balaz M., Oetiker N., Wagen F., Wolfrum C., Simon A.K., Joller N., Barral Y., Spörri R., Oxenius A. Asymmetric cell division shapes naive and virtual memory T-cell immunity during ageing. Nat. Commun., 2021, Vol. 12, no. 1, 2715. doi: 10.1038/s41467-021-22954-y.Chaki B., Pal S., Chattopadhyay S., Bandyopadhyay A. Influence of puberty on high intensity exercise induced skeletal muscle damage and inflammatory response in sedentary boys. Sports Med. Health Sci., 2024, Vol. 7, no. 2, pp. 116-123.Chen L., Wang S., Wang Y., Zhang W., Ma K., Hu C., Zhu H., Liang S., Liu M., Xu N. IL-6 influences the polarization of macrophages and the formation and growth of colorectal tumor. Oncotarget, 2018, Vol. 9, no. 25, pp. 17443-17454.Chen P.W., Hsu C.C., Lai L.F., Chi C.P., Yu S.H. Effects of hypoxia-hyperoxia preconditioning on indicators of muscle damage after acute resistance exercise in male athletes. Front. Physiol., 2022, Vol. 13, 824210. doi: 10.3389/fphys.2022.824210.Chow L.S., Gerszten R.E., Taylor J.M., Pedersen B.K., van Praag H., Trappe S., Febbraio M.A., Galis Z.S., Gao Y., Haus J.M., Lanza I.R., Lavie C.J., Lee C.H., Lucia A., Moro C., Pandey A., Robbins J.M., Stanford K.I., Thackray A.E., Villeda S., Snyder M.P. (2022). Exerkines in health, resilience and disease. Nat. Rev. Endocrinol., 2022, Vol. 18, no. 5, pp. 273-289.Cortes-Canteli M., Iadecola C. Alzheimer’s Disease and Vascular Aging: JACC Focus Seminar. J. Am. Coll. Cardiol., 2020, Vol. 75, no. 8, pp. 942-951.Dantas W.S., Neves W.D., Gil S., Barcellos C.R.G., Rocha M.P., de Sá-Pinto A.L., Roschel H., Gualano B. Exercise-induced anti-inflammatory effects in overweight/obese women with polycystic ovary syndrome. Cytokine, 2019, Vol. 120, pp. 66-70.Docherty S., Harley R., McAuley J.J., Crowe L.A.N., Pedret C., Kirwan P.D., Siebert S., Millar N.L. The effect of exercise on cytokines: implications for musculoskeletal health: a narrative review. BMC Sports Sci. Med. Rehabil., 2022, Vol. 14, no. 1, 5. doi: 10.1186/s13102-022-00397-2.Ferreira V.L., Borba H., Bonetti A.F., Leonart L., Pontarolo R. Cytokines and Interferons: Types and Functions. In: Khan W.A. (ed.). Autoantibodies and Cytokines. 2019.Forcina L., Cosentino M., Musarò A. Mechanisms regulating muscle regeneration: insights into the interrelated and time-dependent phases of tissue healing. Cells, 2020, Vol. 9, no. 5, 1297. doi: 10.3390/cells9051297.Forcina L., Franceschi C., Musarò A. The hormetic and hermetic role of IL-6. Ageing Res. Rev., 2022, Vol. 80, 101697. doi: 10.1016/j.arr.2022.101697.Forcina L., Musarò, A. Rejuvenating muscle stem cells with the glutathione system. Cell Metab., 2023, Vol. 35, no. 3, pp. 379-381.Goj T., Hoene M., Fritsche L., Schneeweiss P., Machann J., Petrera A., Hauck S.M., Fritsche A., Birkenfeld A.L., Peter A., Heni M., Niess A.M., Moller A., Weigert C. The Acute Cytokine Response to 30-minute exercise bouts before and after 8-week endurance training in individuals with obesity. J. Clin. Endocrinol. Metab., 2023, Vol. 108, no. 4, pp. 865-875.Gómez-Rubio P., Trapero I. The effects of exercise on IL-6 levels and cognitive performance in patients with schizophrenia. Diseases, 2019, Vol. 7, no. 1, 11. doi: 10.3390/diseases7010011.Grunewald M., Kumar S., Sharife H., Volinsky E., Gileles-Hillel A., Licht T., Permyakova A., Hinden L., Azar S., Friedmann Y., Kupetz P., Tzuberi R., Anisimov A., Alitalo K., Horwitz M., Leebhoff S., Khoma OZ., Hlushchuk R., Djonov V., Abramovitch R., Tam J., Keshet E. Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span. Science, 2021, Vol. 373, no. 6554, eabc8479. doi: 10.1126/science.abc8479.Guo J., Huang X., Dou L., Yan M., Shen T., Tang W., Li J. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct. Target. Ther., 2022, Vol. 7, no. 1, 391. doi: 10.1038/s41392-022-01251-0.Hernández Cordero A.I., Yang C.X., Yang J., Horvath S., Shaipanich T., MacIsaac J., Lin D.T.S., Kobor M.S., Guillemi S., Harris M., Lam W., Lam S., Montaner J., Man S.F.P., Sin D.D., Leung J.M. Airway aging and methylation disruptions in HIV-associated chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., 2022, Vol. 206, no. 2, pp. 150-160.Islam H., Tsai S.H., Figueiredo C., Jackson G.S., Marcotte-Chénard A., Bosak J., Moreno-Cabañas A., Lira F.S., Little J.P. Direct assessment of leukocyte signalling and cytokine secretion reveals exercise intensity-dependent reductions in anti-inflammatory cytokine action. J. Physiol., 2024, Vol. 602, no. 12, pp. 2717-2736.Jenkins D.E., Sreenivasan D., Carman F., Samal B., Eiden L.E., Bunn S.J. Interleukin-6-mediated signaling in adrenal medullary chromaffin cells. J. Neurochem., 2016, Vol. 139, no. 6, pp. 1138-1150.Karavasiloglou N., Thompson A.S., Pestoni G., Knuppel A., Papier K., Cassidy A., Kühn T., Rohrmann S. Adherence to the EAT-Lancet reference diet is associated with a reduced risk of incident cancer and all-cause mortality in UK adults. One Earth, 2023, Vol. 6, no. 12, pp. 1726-1734.Katayama K., Saito M. Muscle sympathetic nerve activity during exercise. J. Physiol. Sci., 2019, Vol. 69, no. 4, pp. 589-598.Kolasa-Trela R., Konieczynska M., Bazanek M., Undas A. Specific changes in circulating cytokines and growth factors induced by exercise stress testing in asymptomatic aortic valve stenosis. PloS ONE, 2017, Vol. 12, no. 3, e0173787. doi: 10.1371/journal.pone.0173787.Kooti M., Soori R., Shabkhiz F., Pournemati P. The Effect of Three Month Combined Training on the Serum Levels of Interleukin-6 and C-Reactive Protein in Sedentary Obese Women. J. Basic Res. Med. Sci., 2022, Vol. 9, no. 4, pp. 34-44.Kruk J., Aboul-Enein H.Y., Kładna A., Bowser J.E. Oxidative stress in biological systems and its relation with pathophysiological functions: the effect of physical activity on cellular redox homeostasis. Free Radic. Res., 2019, Vol. 53, no. 5, pp. 497-521.Lauritzen H.P., Brandauer J., Schjerling P., Koh H.J., Treebak J.T., Hirshman M.F., Galbo H., Goodyear L.J. Contraction and AICAR stimulate IL-6 vesicle depletion from skeletal muscle fibers in vivo. Diabetes, 2013, Vol. 62, no. 9, pp. 3081-3092.Lin C., Li D., Wang X., Yang S. Chronic exercise interventions for executive function in overweight children: a systematic review and meta-analysis. Front. Sports Act. Living, 2024, Vol. 6, 1336648. doi: 10.3389/fspor.2024.1336648.Liu T., Zhang L., Joo D., Sun S.C. NF-κB signaling in inflammation. Signal Transduct. Target. Ther., 2017, Vol. 2, 17023. doi: 10.1038/sigtrans.2017.23.Makiel K., Suder A., Targosz A., Maciejczyk M., Haim A. Exercise-induced alternations of adiponectin, interleukin-8 and indicators of carbohydrate metabolism in males with metabolic syndrome. Biomolecules, 2023, Vol. 13, no. 5, 852. doi: 10.3390/biom13050852.McDougle J.M., Mangine G.T., Townsend J.R., Jajtner A.R., Feito Y. Acute physiological outcomes of high-intensity functional training: a scoping review. PeerJ, 2023, Vol. 11, e14493. doi: 10.7717/peerj.14493.Metcalfe R.D., Putoczki T.L., Griffin M.D.W. Structural understanding of interleukin 6 family cytokine signaling and targeted therapies: focus on interleukin 11. Front. Immunol., 2020, Vol. 11, 1424. doi: 10.3389/fimmu.2020.01424.Nash D., Hughes M.G., Butcher L., Aicheler R., Smith P., Cullen T., Webb R. IL-6 signaling in acute exercise and chronic training: Potential consequences for health and athletic performance. Scand. J. Med. Sci. Sports, 2023, Vol. 33, no. 1, pp. 4-19.Olson E.N., Williams R.S. Calcineurin signaling and muscle remodeling. Cell, 2000, Vol. 101, no. 7, pp. 689-692.Orange S.T., Leslie J., Ross M., Mann D.A., Wackerhage H. The exercise IL-6 enigma in cancer. Trends Endocrinol. Metab., 2023, Vol. 34, no. 11, pp. 749-763.Ostrowski K., Hermann C., Bangash A., Schjerling P., Nielsen J.N., Pedersen B.K. A trauma-like elevation of plasma cytokines in humans in response to treadmill running. J. Physiol., 1998, Vol. 513, no. 3, pp. 889-894.Piccirillo R. Exercise-induced myokines with therapeutic potential for muscle wasting. Front. Physiol., 2019. Vol. 10, 287. doi: 10.3389/fphys.2019.00287.Proschinger S., Schenk A., Weßels I., Donath L., Rappelt L., Metcalfe A. J., Zimmer P. Intensity- and time-matched acute interval and continuous endurance exercise similarly induce an anti-inflammatory environment in recreationally active runners: focus on PD-1 expression in Tregs and the IL-6/IL-10 axis. Eur. J. Appl. Physiol., 2023, Vol. 123, no. 11, pp. 2575-2584.Recchia F., Leung C.K., Yu A.P., Leung W., Yu D.J., Fong D.Y., Montero D., Lee C.H., Wong S.H.S., Siu P.M. Dose-response effects of exercise and caloric restriction on visceral adiposity in overweight and obese adults: a systematic review and meta-analysis of randomised controlled trials. Br. J. Sports Med., 2023, Vol. 57, no. 16, pp. 1035-1041.Reihmane D., Dela F. Interleukin-6: possible biological roles during exercise. Eur. J. Sport Sci., 2014, Vol. 14, no. 3, pp. 242-250.Rodrigues L.P., Teixeira V.R., Alencar-Silva T., Simonassi-Paiva B., Pereira R.W., Pogue R., Carvalho J.L. Hallmarks of aging and immunosenescence: Connecting the dots. Cytokine Growth Factor Rev., 2021, Vol. 59, pp. 9-21.Sabaratnam R., Pedersen A.J.T., Kristensen J.M., Handberg A., Wojtaszewski J.F.P., Højlund K. Intact regulation of muscle expression and circulating levels of myokines in response to exercise in patients with type 2 diabetes. Physiol. Rep., 2018, Vol. 6, no. 12, e13723. doi: 10.14814/phy2.13723.Santoro A., Bientinesi E., Monti D. Immunosenescence and inflammaging in the aging process: age-related diseases or longevity? Ageing Res. Rev., 2021, Vol. 71, 101422. doi: 10.1016/j.arr.2021.101422.Santoro A., Martucci M., Conte M., Capri M., Franceschi C., Salvioli S. Inflammaging, hormesis and the rationale for anti-aging strategies. Ageing Res. Rev., 2020, Vol. 64, 101142. doi: 10.1016/j.arr.2020.101142.Shamsnia E., Matinhomaee H., Azarbayjani M.A., Peeri M. The Effect of aerobic exercise on oxidative stress in skeletal muscle tissue: a narrative review. Gene Cell Tissue, 2023, Vol. 10, no. 4, e131964. doi: 10.5812/gct-131964.Soares V., Silveira de Avelar I., Espíndola Mota Venâncio P., Pires-Oliveira D.A.A., de Almeida Silva P.H., Rodrigues Borges A., Fonseca G.P.E.F., Noll M. Acute changes in interleukin-6 level during four days of long-distance walking. J. Inflamm. Res., 2020. Vol. 13, pp. 871-878.Steensberg A., Fischer C.P., Keller C., Møller K., Pedersen B.K. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. American journal of physiology. Endocrinol. Metab., 2023, Vol. 285, no. 2, pp. E433-E437.Steensberg A., Keller C., Hillig T., Frøsig C., Wojtaszewski J.F., Pedersen B.K., Pilegaard H., Sander M. Nitric oxide production is a proximal signaling event controlling exercise-induced mRNA expression in human skeletal muscle. FASEB J., 2007, Vol. 21, no. 11, pp. 2683-2694.Suzuki K., Tominaga T., Ruhee R.T., Ma S. Characterization and modulation of systemic inflammatory response to exhaustive exercise in relation to oxidative stress. Antioxidants, 2020, Vol. 9, no. 5, 401. doi: 10.3390/antiox9050401.Tan B.L., Norhaizan M.E., Liew W.P., Sulaiman Rahman, H. Antioxidant and oxidative stress: a mutual interplay in age-related diseases. Front. Pharmacol., 2018, Vol. 9, 1162. doi: 10.3389/fphar.2018.01162.Toft A.D., Falahati A., Steensberg A. Source and kinetics of interleukin-6 in humans during exercise demonstrated by a minimally invasive model. Eur. J. Appl. Physiol., 2011, Vol. 111, no. 7, pp. 1351-1359.Tu H., Li Y.L. Inflammation balance in skeletal muscle damage and repair. Front. Immunol., 2023, Vol. 14, 1133355. doi: 10.3389/fimmu.2023.1133355.Villar-Fincheira P., Paredes A.J., Hernández-Díaz T., Norambuena-Soto I., Cancino-Arenas N., Sanhueza-Olivares F., Contreras-Briceño F., Mandiola J., Bruneau N., García L., Ocaranza M.P., Troncoso R., Gabrielli L., Chiong M. Soluble interleukin-6 receptor regulates interleukin-6-dependent vascular remodeling in long-distance runners. Front. Physiol., 2021, Vol. 12, 722528. doi: 10.3389/fphys.2021.722528.Villar-Fincheira P., Sanhueza-Olivares F., Norambuena-Soto I., Cancino-Arenas N., Hernandez-Vargas F., Troncoso R., Gabrielli L., Chiong M. Role of interleukin-6 in vascular health and disease. Front. Mol. Biosci., 2021, Vol. 8, 641734. doi: 10.3389/fmolb.2021.641734.Wang Q., Zhou W. Roles and molecular mechanisms of physical exercise in cancer prevention and treatment. J. Sport Health Sci., 2021, Vol. 10, no. 2, pp. 201-210.Xu Y., Liu X., Tsuji K., Hamaoka T., Tabata I. Oxygen uptake during the last bouts of exercise incorporated into high-intensity intermittent cross-exercise exceeds the V˙ O2max of the same exercise mode. Sports Med. Health Sci., 2024, Vol. 6, no. 1, pp. 63-69.Yan M., Sun S., Xu K., Huang X., Dou L., Pang J., Tang W., Shen T., Li J. Cardiac aging: from basic research to therapeutics. Oxid. Med. Cell. Longev., 2021, Vol. 9, 9570325. doi: 10.1155/2021/9570325.