Targeted protein degradation (TPD) technologies leverage the body’s innate protein degradation systems to selectively eliminate protein of interest (POI). This technology overcomes the limitations of the traditional “site-occupancy” approach (whereby a drug directly binds to the active site of the protein of POI to inhibit its function), instead adopting an “event-driven” approach (whereby the drug indirectly eliminates the POI by triggering specific biological events such as ubiquitination or lysosomal degradation) to catalyze the degradation of the POI rather than inhibiting its function. TPD technology offers significant advantages, including the ability to target “undruggable” proteins, rapid action, high selectivity and the ability to overcome drug resistance, and has become a leading frontier in the field of drug discovery in recent years. Currently, the main TPD technological pathways include degradation pathways based on the ubiquitin-proteasome system, the endosomes-lysosomal degradation system, and the autophagy pathway. This paper aims to provide a reference for future research by reviewing the latest developments in TPD  technology.

1. Pietzner M, Wheeler E, Carrasco-Zanini J, et al. Mapping the proteo-genomic convergence of human diseases[J]. Science, 2021, 374(6569): eabj1541.

2. Sun J, Luo J, Jiang F, et al. Exploring the cross-cancer effect of circulating proteins and discovering potential intervention targets for 13 site-specific cancers[J]. J Natl Cancer Inst, 2024, 116(4): 565-573.

3. Lee SH, Park SY, Choi CS. Insulin resistance: from mechanisms to therapeutic strategies[J]. Diabetes Metab J, 2022, 46(1): 15-37.

4. Zhang H, Wei W, Zhao M, et al. Interaction between Aβ and Tau in the pathogenesis of Alzheimer's disease[J]. Int J Biol Sci, 2021, 17(9): 2181-2192.

5. Jin Y, Du Q, Song M, et al. Amyloid-β-targeting immunotherapies for Alzheimer's disease[J]. J Control Release, 2024, 375: 346-365.

6. Peng Y, Wang Y, Zhou C, et al. PI3K/Akt/mTOR pathway and its role in cancer therapeutics: are we making headway?[J]. Front Oncol, 2022, 12: 819128.

7. Sharma KR, Colvis CM, Rodgers GP, et al. Illuminating the druggable genome: pathways to progress[J]. Drug Discov Today, 2024, 29(3): 103805.

8. Leonetti A, Sharma S, Minari R, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer[J]. Br J Cancer, 2019, 121(9): 725-737.

9. Elshatlawy M, Sampson J, Clarke K, et al. EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries[J]. Mol Oncol, 2023, 17(6): 950-963.

10. Zhong G, Chang X, Xie W, et al. Targeted protein degradation: advances in drug discovery and clinical practice[J]. Signal Transduct Target Ther, 2024, 9(1): 308.

11. Sun Y, Ding N, Song Y, et al. Degradation of Bruton's tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas[J]. Leukemia, 2019, 33(8): 2105-2110.

12. Shorer Arbel Y, Katz BZ, Gabizon R, et al. Proteolysis targeting chimeras for BTK efficiently inhibit B-cell receptor signaling and can overcome ibrutinib resistance in CLL cells[J]. Front Oncol, 2021, 11: 646971.

13. Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm[J]. Nat Rev Drug Discov, 2017, 16(2): 101-114.

14. Wu S, Jiang Y, Hong Y, et al. BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes[J]. Cancer Cell Int, 2021, 21(1): 230.

15. Dale B, Cheng M, Park KS, et al. Advancing targeted protein degradation for cancer therapy[J]. Nat Rev Cancer, 2021, 21(10): 638-654.

16. Zhao L, Zhao J, Zhong K, et al. Targeted protein degradation: mechanisms, strategies and application[J]. Signal Transduct Target Ther, 2022, 7(1): 113.

17. Ao N, Chen Q, Liu G. The small molecules targeting ubiquitin-proteasome system for cancer therapy[J]. Comb Chem High Throughput Screen, 2017, 20(5): 403-413.

18. Gu S, Cui D, Chen X, et al. PROTACs: an emerging targeting technique for protein degradation in drug discovery[J]. Bioessays, 2018, 40(4): e1700247.

19. Li K, Crews CM. PROTACs: past, present and future[J]. Chem Soc Rev, 2022, 51(12): 5214-36.

20. Wang Y, Jiang XY, Feng F, et al. Degradation of proteins by PROTACs and other strategies[J]. Acta Pharmacol Sin B, 2020, 10(2): 207-238.

21. Yang Q, Zhao J, Chen D, et al. E3 ubiquitin ligases: styles, structures and functions[J]. Mol Biomed, 2021, 2(1): 23.

22. Alabi SB, Crews CM. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs[J]. J Biol Chem, 2021, 296: 100647.

23. Schneekloth AR, Pucheault M, Tae HS, et al. Targeted intracellular protein degradation induced by a small molecule: en route to chemical proteomics[J]. Bioorg Med Chem Lett, 2008, 18(22): 5904-5908.

24. Schapira M, Calabrese MF, Bullock AN, et al. Targeted protein degradation: expanding the toolbox[J]. Nature Reviews Drug Discovery, 2019, 18(12): 949-963.

25. Zeng S, Huang W, Zheng X, et al. Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: recent progress and future challenges[J]. Eur J Med Chem, 2021, 210: 112981.

26. Schreiber SL. The rise of molecular glues[J]. Cell, 2021, 184(1): 3-9.

27. Lemaitre T, Cornu M, Schwalen F, et al. Molecular glue degraders: exciting opportunities for novel drug discovery[J]. Expert Opin Drug Discov, 2024, 19(4): 433-449.

28. Tan X, Huang Z, Pei H, et al. Molecular glue-mediated targeted protein degradation: a novel strategy in small-molecule drug development[J]. iScience, 2024, 27(9): 110712.

29. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity[J]. Science, 2010, 327(5971): 1345-1350.

30. Ito T, Handa H. Molecular mechanisms of thalidomide and its derivatives[J]. Proc Jpn Acad Ser B Phys Biol Sci, 2020, 96(6): 189-203.

31. Asatsuma-Okumura T, Ito T, Handa H. Molecular mechanisms of cereblon-based drugs[J]. Pharmacol Ther, 2019, 202: 132-139.

32. Beechinor RJ, Mohyuddin GR, Mitchell DE, et al. The story of the development of generic lenalidomide: how one company thwarted the Hatch-Waxman Act to generate billions of dollars in revenue[J]. J Cancer Policy, 2023, 38: 100446.

33. Fuchs O. Targeting cereblon in hematologic malignancies[J]. Blood Rev, 2023, 57: 100994.

34. Verano AL, You I, Donovan KA, et al. Redirecting the neo-substrate specificity of cereblon-targeting PROTACs to helios[J]. ACS Chem Biol, 2022, 17(9): 2404-2410.

35. Jeger JL. Endosomes, lysosomes, and the role of endosomal and lysosomal biogenesis in cancer development[J]. Mol Biol Rep, 2020, 47(12): 9801-9810.

36. Banik SM, Pedram K, Wisnovsky S, et al. Lysosome-targeting chimaeras for degradation of extracellular proteins[J]. Nature, 2020, 584(7820): 291-297.

37. Wu Y, Lin B, Lu Y, et al. Aptamer-LYTACs for targeted degradation of extracellular and membrane proteins[J]. Angew Chem Int Ed Engl, 2023, 62(15): e202218106.

38. Uhlen M, Fagerberg L, Hallstrom BM, et al. Proteomics. Tissue-based map of the human proteome[J]. Science, 2015, 347(6220): 1260419.

39. Caianiello DF, Zhang M, Ray JD, et al. Bifunctional small molecules that mediate the degradation of extracellular proteins[J]. Nat Chem Biol, 2021, 17(9): 947-953.

40. Howell RA, Wang S, Khambete M, et al. Bifunctional molecules that induce both targeted degradation and transcytosis of extracellular proteins in brain cells[J]. J Am Chem Soc, 2024, 146(24): 16404-16411.

41. Ahn G, Banik SM, Miller CL, et al. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation[J]. Nat Chem Biol, 2021, 17(9): 937-946.

42. Liu S, Yao S, Yang H, et al. Autophagy: regulator of cell death[J]. Cell Death Dis, 2023, 14(10): 648.

43. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms[J]. J Pathol, 2010, 221(1): 3-12.

44. Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae[J]. FEBS Lett, 1993, 333(1-2): 169-174.

45. Shao J, Xie S, Hong S, et al. Autophagy-mediated targeted protein degradation[J]. ChemMedChem, 2025, 20(6): e202400866.

46. Zhang J, Pan X, Ji W, et al. Autophagy mediated targeting degradation, a promising strategy in drug development[J]. Bioorg Chem, 2024, 149: 107466.

47. Takahashi D, Moriyama J, Nakamura T, et al. AUTACs: cargo-specific degraders using selective autophagy[J]. Mol Cell, 2019, 76(5): 797-810. e10.

48. Takahashi D, Arimoto H. Targeting selective autophagy by AUTAC degraders[J]. Autophagy, 2020, 16(4): 765-766.

49. Takahashi D, Ora T, Sasaki S, et al. Second-generation autacs for targeted autophagic degradation[J]. J Med Chem, 2023, 66(17): 12342-12372.

50. Yamamoto H, Matsui T. Molecular mechanisms of macroautophagy, microautophagy, and chaperone-mediated autophagy[J]. J Nippon Med Sch, 2024, 91(1): 2-9.

51. Magalhaes JD, Fao L, Vilaca R, et al. Macroautophagy and mitophagy in neurodegenerative disorders: focus on therapeutic interventions[J]. Biomedicines, 2021, 9(11): 1625.

52. Murley A, Popovici AC, Hu XS, et al. Quiescent cell re-entry is limited by macroautophagy-induced lysosomal damage[J]. Cell, 2025, 188(10): 2670-2686. e14.

53. Winter GE, Buckley DL, Paulk J, et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation[J]. Science, 2015, 348(6241): 1376-1381.

54. Li Z, Zhu C, Ding Y, et al. ATTEC: a potential new approach to target proteinopathies[J]. Autophagy, 2020, 16(1): 185-187.

55. Zhang K, Zhu S, Li J, et al. Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease[J]. Acta Pharm Sin B, 2021, 11(10): 3015-3034.

56. Dong G, Wu Y, Cheng J, et al. Ispinesib as an effective warhead for the design of autophagosome-tethering chimeras: discovery of potent degraders of nicotinamide phosphoribosyl transferase (NAMPT)[J]. J Med Chem, 2022, 65(11): 7619-7628.

57. Zhu Z, Li J, Shen S, et al. Targeting EGFR degradation by autophagosome degraders[J]. Eur J Med Chem, 2024, 270: 116345.

58. Li S, Zeng T, Wu Z, et al. DNA tetrahedron-driven multivalent proteolysis-targeting chimeras: enhancing protein degradation efficiency and tumor targeting[J]. J Am Chem Soc, 2025, 147(2): 2168-2181.

59. Zhang X, Simon GM, Cravatt BF. Implications of frequent hitter E3 ligases in targeted protein degradation screens[J]. Nat Chem Biol, 2025, 21(4): 474-481.

60. Zhang X, Luukkonen LM, Eissler CL, et al. DCAF11 supports targeted protein degradation by electrophilic proteolysis-targeting chimeras[J]. J Am Chem Soc, 2021, 143(13): 5141-5149.

61. Campos MA, Riha IA, Zhang C, et al. Discovery of DCAF16 binders for targeted protein degradation[J]. ACS Chem Biol, 2025, 20(2): 479-488.

62. Son SH, Lee NR, Gee MS, et al. Chemical knockdown of phosphorylated p38 mitogen-activated protein kinase (MAPK) as a novel approach for the treatment of Alzheimer's disease[J]. ACS Cent Sci, 2023, 9(3): 417-426.

63. Yan K, He W, Pang M, et al. E3Docker: a docking server for potential E3 binder discovery[J]. Nucleic Acids Res, 2025, 53(W1): W266-W272.

64. Ge R, Chen M, Wu S, et al. DNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases[J]. Nat Commun, 2025, 16(1): 4683.