Multiple preclinical studies sharpen mechanistic maps of how innate immune proteins can suppress hepatitis B virus replication and transcriptional activity. Fujian Medical University reported that TRIM22 blocks HBV replication by tagging LDHA for destruction, connecting cellular metabolism to antiviral signaling outcomes. Separately, a study highlighted IFI35’s role in silencing HBV by degrading HNF4α, a master transcription factor involved in viral cccDNA transcription regulation. Together, the findings point to host-pathway vulnerabilities that can be leveraged for HBV therapy beyond suppression of viral proteins. These results are relevant for pipeline strategy because they identify cellular targets that could complement nucleos(t)ide analogs, potentially addressing the residual viral transcriptional activity that continues in chronic infection. While both papers remain mechanism-focused, they strengthen the rationale for therapies aiming to reactivate immune control of HBV transcriptional machinery.